New derivatives of N-(iminomethyl)amines, their preparation, their use as medicaments and the pharmaceutical compositions containing them

ABSTRACT

N-(imino)amines and their preparation and their use as NO synthase inhibitors and selective or non-selective traps for a reactive oxygen species.

This application is a division of U.S. patent application Ser. No.09/787,466 filed Mar. 16, 2001, now U.S. Patent No. ______, which is a371 of PCT/FR99/02251 filed Sept. 22, 1999.

A subject of the present invention is new derivatives ofN-(iminomethyl)amines comprising the aminodiphenylamine,oxodiphenylamine, carbazole, phenazine, phenothiazine, phenoxazine oroxodiphenyl unit in their skeleton. These derivatives have an inhibitoryactivity on NO-synthase enzymes producing nitrogen monoxide NO and/or anactivity which traps the reactive oxygen species (ROS). The inventionrelates to the derivatives corresponding to general formula (I) definedbelow, their preparation methods, the pharmaceutical preparationscontaining them and their use for therapeutic purposes, in particulartheir use as NO-synthase inhibitors and selective or non selective trapsfor reactive oxygen species.

Given the potential role of NO and the ROS's in physiopathology, the newderivatives described corresponding to general formula (I) may producebeneficial or favourable effects in the treatment of pathologies wherethese chemical species are involved. In particular:

-   -   Proliferative and inflammatory diseases such as for example        atherosclerosis, pulmonary hypertension, respiratory distress,        glomerulonephritis, portal hypertension, psoriasis, arthrosis        and rheumatoid arthritis, fibroses, angiogenisis, amyloidoses,        inflammations of the gastro-intestinal system (ulcerous or        non-ulcerous colitis, Crohn's disease), diarrhoea.    -   Diseases affecting the pulmonary system and airways (asthma,        sinusitis, rhinitis).    -   Cardio-vascular and cerebro-vascular disorders including for        example, migraine, arterial hypertension, septic shock, ischemic        or hemorragic, cardiac or cerebral infarctions, ischemias and        thromboses.    -   Disorders of the central or peripheral nervous system such as        for example neurodegenerative diseases where there can in        particular be mentioned cerebral infarctions, sub-arachnoid        haemorrhaging, ageing, senile dementias including Alzheimer's        disease, Huntington's chorea, Parkinson's disease, Creutzfeld        Jacob disease and prion diseases, amyotrophic lateral sclerosis;        ocular neuropathies such as glaucoma but also pain, cerebral and        bone marrow traumas, addiction to opiates, alcohol and addictive        substances, cognitive disorders, encephalopathies,        encephalopathies of viral or toxic origin.    -   Disorders of the skeletal muscle and neuromuscular joints        (myopathy, myosis) as well as cutaneous diseases.    -   Cataracts.    -   Organ transplants.    -   Auto-immune and viral diseases such as for example lupus, AIDS,        parasitic and viral infections, diabetes and its complications,        multiple sclerosis.    -   Cancer.    -   Neurological diseases associated with intoxications (Cadmium        poisoning, inhalation of n-hexane, pesticides, herbicides),        associated with treatments (radiotherapy) or disorders of        genetic origin (Wilson's disease).    -   all the pathologies characterized by an excessive production or        dysfunction of NO and/or ROS's.

In all these pathologies, there is experimental evidence demonstratingthe involvement of NO or ROS's (J. Med. Chem. (1995) 38, 4343-4362; FreeRadic. Biol. Med. (1996) 20, 675-705; The Neuroscientist (1997) 3,327-333).

Moreover, in earlier patents, the inventors have already described NOSynthase inhibitors and their use (U.S. Pat. Nos. 5,081,148; 5,360,925)and more recently the combination of these inhibitors with productshaving antioxidant or antiradicular properties (Patent Application PCTWO/09653). They have also described in not yet published Applicationsother derivatives of amidines or, more recently, derivatives ofaminopyridines. These derivatives of amidines or aminopyridines have thecharacteristic of being both NO Synthase inhibitors and ROS inhibitors.

A subject of the present invention is new derivatives of amidines, theirpreparation and their use in therapeutics.

The compounds of the invention correspond to general formula (I):

in which

-   -   Φ represents a bond or a phenylene radical which can include, in        addition to the two chains already represented in general        formula (I), up to two substituents chosen from a hydrogen atom,        a halogen, an OH group, and a linear or branched alkyl or alkoxy        radical having 1 to 6 carbon atoms;    -   A represents a    -   radical in which R₁, R₂, R₃, R₄, R₅ represent, independently, a        hydrogen atom, a halogen, the OH group, a linear or branched        alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano,        nitro or NR₆R₇ radical,    -   R₆ and R₇ representing, independently, a hydrogen atom, the OH        group, a linear or branched alkyl or alkoxy radical having 1 to        6 carbon atoms, or also a —COR₈ group,    -   R₈ representing a hydrogen atom, the OH group, a linear or        branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or        NR₉R₁₀,    -   R₉ and R₁₀ representing, independently, a hydrogen atom, the OH        group or a linear or branched alkyl radical having 1 to 6 carbon        atoms,    -   R₁₁ representing a hydrogen atom, the OH group, a linear or        branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or        a —COR₁₂ radical,    -   and R₁₂ representing a hydrogen atom, the OH group, a linear or        branched alkyl radical having 1 to 6 carbon atoms,    -   or a    -   radical in which R₁, R₂, R₃, R₄, R₅ represent, independently, a        hydrogen atom, a halogen, the OH group, a linear or branched        alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano,        nitro or NR₆R₇ radical,    -   R₆ and R₇ representing, independently, a hydrogen atom, the OH        group, a linear or branched alkyl or alkoxy radical having 1 to        6 carbon atoms, or also a —COR₈ group,    -   R₈ representing a hydrogen atom, the OH group, a linear or        branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or        NR₉R₁₀,    -   R₉ and R₁₀ representing, independently, a hydrogen atom, the OH        group or a linear or branched alkyl radical having 1 to 6 carbon        atoms,    -   B represents —CH₂—NO₂, a linear or branched alkyl radical having        1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or        6 members containing 1 to 4 heteroatoms chosen from O, S, N and        in particular the thiophene, furan, pyrrole or thiazole radical,        the aryl radical being optionally substituted by one or more        groups chosen from linear or branched alkyl, alkenyl or alkoxy        radicals having 1 to 6 carbon atoms,    -   or B represents an NR₁₃R₁₄ radical, in which R₁₃ and R₁₄        representing, independently, a hydrogen atom or a linear or        branched alkyl radical having 1 to 6 carbon atoms or a cyano or        nitro radical, or R₁₃ and R₁₄ form with the nitrogen atom a non        aromatic heterocycle with five to six members, the elements of        the chain being chosen from a group composed of —CH₂—, —NH—, —O—        or —S—;    -   W does not exist, or represents a bond, or O, S or NR₁₅, in        which R₁₅ represents a hydrogen atom or a linear or branched        alkyl radical having 1 to 6 carbon atoms;    -   X represents a bond or a (CH₂)_(k)—NR₁₆—, —O—, —S—, —CO—,        —NR₁₆—CO—, —CO—NR₁₆—, —O—CO—, —CO—O—, —NR₁₆—CO—O—,        —NR₁₆—CO—NR₁₇— radical,    -   k representing 0 or 1;    -   Y represents a bond or a radical chosen from the —(CH₂)_(m))—,        —(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,        —(CH₂)_(m)—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)—,        —(CH₂)_(m)—CO—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—Q—(CH₂)_(n)— radicals,    -   Q representing piperazine, homopiperazine, 2-methylpiperazine,        2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine        radicals,    -   m and n being integers from 0 to 6;    -   R₁₆, R₁₇ and R₁₈ represent, independently, a hydrogen atom or a        linear or branched alkyl radical having 1 to 6 carbon atoms;    -   or are salts of the products mentioned previously.

By linear or branched alkyl having 1 to 6 carbon atoms, is meant inparticular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexylradicals. By linear or branched alkoxy having 1 to 6 carbon atoms, ismeant the alkyl radical of which has the meaning indicated previously.Finally, by halogen, is meant fluorine, chlorine, bromine or iodineatoms.

Preferably, the compounds according to the invention are the compoundsof general formula (I) such that:

-   -   A represents a    -   radical in which R₁, R₂, R₃, R₄, R₅ represent, independently, a        hydrogen atom, the OH group or a linear or branched alkyl or        alkoxy radical having 1 to 6 carbon atoms,    -   R₁₁ representing a hydrogen atom or a linear or branched alkyl        radical having 1 to 6 carbon atoms,    -   or a    -   radical in which R₁, R₂, R₃, R₄, R₅ represent, independently, a        hydrogen atom, the OH group or a linear or branched alkyl or        alkoxy radical having 1 to 6 carbon atoms;    -   B represents a carbocyclic or heterocyclic aryl radical with 5        or 6 members containing 1 to 4 heteroatoms chosen from O, S, N        and in particular the thiophene, furan, pyrrole or thiazole        radicals, the aryl radical being optionally substituted by one        or more groups chosen from linear or branched alkyl, alkenyl or        alkoxy radicals having 1 to 6 carbon atoms;    -   W does not exist, or represents a bond, S or NR₁₅, in which R₁₅        represents a hydrogen atom or a linear or branched alkyl radical        having 1 to 6 carbon atoms;    -   X represents a bond or a —(CH₂)_(k)—NR₁₆—, —O—, —S—, —CO—,        —NR₁₆—CO—, —CO—NR₁₆—, —O—CO—, —CO—O—, —NR₁₆—CO—O—,        —NR₁₆—CO—NR₁₇— radical    -   k representing 0 or 1;    -   Y represents a bond or a radical chosen from the —(CH₂)_(m)—,        —(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,        —(CH₂)_(m)—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)—,        —CH₂)_(m)—CO—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—Q—(CH₂)_(n)— radicals,    -   Q representing piperazine, homopiperazine, 2-methylpiperazine,        2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine,    -   m and n being integers from 0 to 6;    -   or are salts of the products mentioned previously.

More preferentially, the compounds according to the invention arecompounds of general formula (I) such that:

-   -   A represents a    -   radical in which R₁, R₂, R₃, R₄ and R₅ represent, independently,        a hydrogen atom, the OH group or a linear or branched alkyl or        alkoxy radical having 1 to 6 carbon atoms,    -   R₁₁ representing a hydrogen atom or a methyl radical,    -   or a    -   radical in which R₁, R₂, R₃, R₄, R₅ represent, independently, a        hydrogen atom, the OH group or a linear or branched alkyl or        alkoxy radical having 1 to 6 carbon atoms;    -   B represents one of the phenyl, thiophene, furan, pyrrole or        thiazole radicals optionally substituted by one or more groups        chosen from linear or branched alkyl, alkenyl or alkoxy radicals        having 1 to 6 carbon atoms;    -   W does not exist, or represents a bond, S or NR₁₅, in which R₁₅        represents a hydrogen atom or a linear or branched alkyl radical        having 1 to 6 carbon atoms;    -   X represents a bond or a —(CH₂)_(k)—NR₁₆—, —O—, —S—, —CO—,        —NR₁₆—CO—, —CO—NR₁₆—, —O—CO—, —CO—O—, —NR₁₆—CO—O—,        —NR₁₆—CO-NR₁₇— radical,    -   k representing 0 or 1;    -   Y represents a bond or a radical chosen from the —(CH₂)_(m)—,        —(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,        —(CH₂)_(m)—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)—,        —(CH₂)_(m)—CO—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—Q—(CH₂)_(n)— radicals,    -   Q representing piperazine, homopiperazine, 2-methylpiperazine,        2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine,    -   m and n being integers comprised from 0 to 6;    -   or are salts of the products mentioned previously.

Yet more preferentially, the compounds according to the invention arecompounds of general formula (I) such that:

-   -   A represents a    -   radical in which R₁, R₂, R₃, R₄, R₅ represent, independently, a        hydrogen atom or a methyl radical,    -   R₁₁ representing a hydrogen atom or a methyl radical;    -   B represents the thiophene radical;    -   W does not exist, represents a single bond or S;    -   X represents a bond or represents a —(CH₂)_(k)—NR₁₆—, —O—, —S—,        —CO—, —NR₁₆—CO—, —CO—NR₁₆—, —O—CO—, —CO—O—, —NR₁₆—CO—O—,        —NR₁₆—CO—NR₁₇— radical;    -   k representing 0 or 1;    -   Y represents a bond or a radical chosen from the —(CH₂)_(m)—,        —(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,        —(CH₂)_(m)—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)—,        —(CH₂)_(m)—CO—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—Q—(CH₂)_(n)— radicals,    -   Q representing piperazine,    -   m and n being integers comprised between 0 and 6;    -   R₁₆, R₁₇ and R₁₈ represent a hydrogen atom;    -   or are salts of the products mentioned previously.

Quite particularly preferred are the following compounds described inthe examples:

-   N-[4-(phenylamino)phenyl]-2-thiophenecarboximidamide;-   4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzeneacetamide;-   {4-{[2-thienyl(imino)methyl]amino}phenoxy}-N-[4-(phenylamino)phenyl]-acetamide;-   4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzenebutanamide;-   4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanamide;-   4-{[2-thienyl(imino)methyl]amino}-N-[4-(4-methoxyphenylamino)phenyl]-benzenebutanamide;-   2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl[4-(phenylamino)phenyl]-carbamate;-   N-{2-{4-{[2-thienyl(imino)methyl]amino}phenyl}ethyl}-N′-[4-(phenylamino)phenyl]-urea;-   4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)phenyl]-1-piperazine-acetamide;-   1-{[(4-phenylamino)phenylamino]carbonyl}-4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-piperazine;-   4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanamine;-   3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenepropanamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)phenyl]butanamide;-   4-anilinophenyl-4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)butanoate;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)phenyl]butanamide;-   N′-{4-[4-(3-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximidamide;-   N′-(9H-carbazol-3-yl)-2-thiophenecarboximidamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(9H-carbazol-3-yl)butanamide;-   N′-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide;-   N′-{4-[(10-methyl-10H-phenothiazin-2-yl)oxy]phenyl}-2-thiophenecarboximidamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazin-3-yl)butanamide;-   N′-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(4-toluidino)phenyl]butanamide;-   3-anilinophenyl    4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)butanoate;-   2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(9H-carbazol-4-yloxy)ethyl]acetamide;-   N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-anilinobenzamide;-   N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-(2,3-dimethylanilino)benzamide;-   N′-{4-[4-(2-anilinobenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;-   N′-(4-{4-[2-(2,3-dimethylanilino)benzoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl)butanamide;-   N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-4-(4-hydroxyphenoxy)benzamide;-   N-[2-(9H-carbazol-4-yloxy)ethyl]-2-thiophenecarboximidamide;-   N-[3-(9H-carbazol-4-yloxy)propyl]-2-thiophenecarboximidamide;-   N-{4-[4-(10H-phenothiazin-2-yloxy)butyl]phenyl}-2-thiophenecarboximidamide;-   3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anilinophenyl)propanamide;-   N′-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;-   N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-methoxy-10H-phenothiazine-1-carboxamide;-   N′-[4-(2-{[(2-methoxy-10H-phenothiazin-1-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;-   N′-{4-[(10H-phenothiazin-2-yloxy)methyl]phenyl}-2-thiophenecarboximidamide;-   or their salts.

Among the exemplified compounds, the following compounds are inparticular preferred:

-   {4-{[2-thienyl(imino)methyl]amino}phenoxy}-N-[4-(phenylamino)phenyl]-acetamide;-   4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzenebutanamide;-   4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanamide;-   2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl    [4-(phenylamino)phenyl]-carbamate;-   4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)phenyl]-1-piperazine-acetamide;-   3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenepropanamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)phenyl]butanamide;-   N′-{4-[4-(3-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximidamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(9H-carbazol-3-yl)butanamide;-   N′-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazin-3-yl)butanamide;-   N′-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl)butanamide;-   3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anilinophenyl)propanamide;-   N′-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;-   N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-methoxy-10H-phenothiazine-1-carboxamide;-   or their salts.

Also more particularly the following compounds are preferred:

-   4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzenebutanamide;-   4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanamide;-   N′-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide;-   4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazin-3-yl)butanamide;-   3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anilinophenyl)propanamide;-   N′-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;-   or their salts.

In a general manner, the compounds of general formula (I) in which Xrepresents a bond or one of the —O—, —CH₂—NR₁₆—, —NR₁₆—CO— or—NR₁₆—CO—O— radicals and Y represents one of the —(CH₂)_(m)— or—(CH₂)_(m)—NR₁₈—(CH₂)_(n)— radicals will be preferred.

In certain cases, the compounds according to the present invention cancontain asymmetrical carbon atoms. As a result, the compounds accordingto the present invention have two possible enantiomeric forms, i.e. “R”and “S” configurations. The present invention includes the twoenantiomeric forms and all combinations of these forms, including theracemic “RS” mixtures. In an effort to simplify matters, when nospecific configuration is indicated in the structural formulae, itshould be understood that the two enantiomeric forms and their mixturesare represented.

The invention further relates, as new industrial products, to thesynthesis intermediates of general formula (IS), useful for thepreparation of products of general formula (I) defined above,A-X-Y-Φ-T  (IS)general formula (IS) in which

-   -   A represents a    -   radical in which R₁, R₂, R₃, R₄, R₅ represent, independently, a        hydrogen atom, a halogen, the OH group, a linear or branched        alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano,        nitro or NR₆R₇ radical,    -   R₆ and R₇ representing, independently, a hydrogen atom, the OH        group, a linear or branched alkyl or alkoxy radical having 1 to        6 carbon atoms, or also a —COR₈ group,    -   R₈ representing a hydrogen atom, the OH group, a linear or        branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or        NR₉R₁₀,    -   R₉ and R₁₀ representing, independently, a hydrogen atom, the OH        group or a linear or branched alkyl radical having 1 to 6 carbon        atoms,    -   R₁₁ representing a hydrogen atom, the OH group, a linear or        branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or        a —COR₁₂ radical,    -   and R₁₂ representing a hydrogen atom, the OH group, a linear or        branched alkyl radical having 1 to 6 carbon atoms,    -   or a    -   radical in which R₁, R₂, R₃, R₄, R₅ represent, independently, a        hydrogen atom, a halogen, the OH group, a linear or branched        alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano,        nitro or NR₆R₇ radical,    -   R₆ and R₇ representing, independently, a hydrogen atom, the OH        group, a linear or branched alkyl or alkoxy radical having 1 to        6 carbon atoms, or also a —COR₈ group,    -   R₈ representing a hydrogen atom, the OH group, a linear or        branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or        NR₉R₁₀,    -   R₉ and R₁₀ representing, independently, a hydrogen atom, the OH        group or a linear or branched alkyl radical having 1 to 6 carbon        atoms;    -   W does not exist, or represents a bond, or O, S or NR₁₅, in        which R₁₅ represents a hydrogen atom or a linear or branched        alkyl radical having 1 to 6 carbon atoms;    -   X represents a bond or a —(CH₂)_(k)—NR₁₆—, —O—, —S—, —CO—,        —NR₁₆—CO—, —CO—NR₁₆—, —O—CO—, —CO—O—, —NR₁₆—CO—O— or        —NR₆—CO—NR₁₇— radical,    -   k representing 0 or 1;    -   Y represents a bond or a radical chosen from the —(CH₂)_(m)—,        —(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,        —(CH₂)_(m)—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)—,        —(CH₂)_(m)—CO—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—Q—(CH₂)_(n)— radicals,    -   Q representing piperazine, homopiperazine, 2-methylpiperazine,        2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine,    -   m and n being integers from 0 to 6;    -   Φ represents a bond or a phenylene radical which may comprise,        in addition to the two chains already represented in general        formula (I), up to two substituents chosen from a hydrogen atom,        a halogen, an OH group and a linear or branched alkyl or alkoxy        radical having 1 to 6 carbon atoms;    -   T represents NO₂ or NH₂;    -   R₁₆, R₁₇ and R₁₈ represent, independently, a hydrogen atom or a        linear or branched alkyl radical having 1 to 6 carbon atoms.

The invention further relates, as new industrial products, to thesynthesis intermediates of general formula (IS′), useful for thepreparation of products of general formula (I) in which X represents the—NR₁₆—CO— radical and Y represents the —(CH₂)_(m)—NR₁₈—(CH₂)_(n)—radical,

general formula (IS′) in which

-   -   A represents a    -   radical in which R₁, R₂, R₃, R₄ and R₅ represent, independently,        a hydrogen atom, a halogen, the OH group, a linear or branched        alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano,        nitro or NR₆R₇ radical,    -   R₆ and R₇ representing, independently, a hydrogen atom, the OH        group, a linear or branched alkyl or alkoxy radical having 1 to        6 carbon atoms, or also a —COR₈ group,    -   R₈ representing a hydrogen atom, the OH group, a linear or        branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or        NR₉R₁₀,    -   R₉ and R₁₀ representing, independently, a hydrogen atom, the OH        group, a linear or branched alkyl radical having 1 to 6 carbon        atoms,    -   R₁₁ representing a hydrogen atom, the OH group, a linear or        branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or        also a —COR₁₂ radical,    -   and R₁₂ representing a hydrogen atom, the OH group, a linear or        branched alkyl radical having 1 to 6 carbon atoms,    -   or a    -   radical in which R₁, R₂, R₃, R₄, R₅ represent, independently, a        hydrogen atom, a halogen, the OH group, a linear or branched        alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano,        nitro or NR₆R₇ radical,    -   R₆ and R₇ representing, independently, a hydrogen atom, the OH        group, a linear or branched alkyl or alkoxy radical having 1 to        6 carbon atoms, or also a —COR₈ group,    -   R₈ representing a hydrogen atom, the OH group, a linear or        branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or        NR_(9R) ₁₀,    -   R₉ et R₁₀ representing, independently, a hydrogen atom, the OH        group, a linear or branched alkyl radical having 1 to 6 carbon        atoms;    -   W does not exist, or represents a bond, or O, S or NR₁₅ in which        R₁₅ represents a hydrogen atom or a linear or branched alkyl        radical having 1 to 6 carbon atoms;    -   π represents a hydrogen atom or a protective group of the        carbamate type;    -   R₁₆, R₁₇ and R₁₈ represent, independently, a hydrogen atom or a        linear or branched alkyl radical having 1 to 6 carbon atoms;    -   and m represents an integer from 0 to 6.

A subject of the invention is also, as medicaments, the compounds ofgeneral formula (I) described previously or their pharmaceuticallyacceptable salts. It also relates to pharmaceutical compositionscontaining these compounds or their pharmaceutically acceptable salts,and the use of these compounds or of their pharmaceutically acceptablesalts for producing medicaments intended to inhibit neuronal NO synthaseor inductible NO synthase, to inhibit lipidic peroxidation or to providethe double function of NO synthase inhibition and lipidic peroxidationinhibition.

By pharmaceutically acceptable salt is meant in particular additionsalts of inorganic acids such as hydrochloride, hydrobromide,hydroiodide sulphate, phosphate, diphosphate and nitrate, or of organicacids, such as acetate, maleate, fumarate, tartrate, succinate, citrate,lactate, methanesulphonate, p-toluenesulphonate, pamoate, oxalate andstearate. The salts formed from bases such as sodium or potassiumhydroxide also fall within the scope of the present invention, when theycan be used. For other examples of pharmaceutically acceptable salts,reference can be made to “Pharmaceutical salts”, J. Pharm. Sci. 66:1(1977).

The pharmaceutical composition can be in the form of a solid, forexample powders, granules, tablets, capsules, liposomes orsuppositories. Appropriate solid supports can be for example calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in the form of a liquid, for example, solutions,emulsions, suspensions or syrups. Appropriate liquid supports can be,for example, water, organic solvents such as glycerol or the glycols, aswell as their mixtures, in varying proportions, in water.

A medicament according to the invention can be administered by topical,oral or parenteral route, by intramuscular injection, etc.

The envisaged administration dose for a medicament according to theinvention is comprised between 0.1 mg and 10 g according to the type ofactive compound used.

In accordance with the invention, the compounds of general formula (I)can be prepared by the process described below.

Preparation of the Compounds of General Formula (I):

The compounds of general formula (I) can be prepared from intermediatesof general formula (II) according to Diagram 1 where A, B, X, Y and Φare as defined above and Gp is a protective group of carbamate type suchas for example the t-butoxycarbonyl group.

The derivatives of aniline of general formula (II), can be condensedwith the compounds of general formula (III), in which L represents aparting group (for example an alkoxy, alkylthio, aralkylthio, sulphonicacid, halide, aryl alcohol or tosyl radical), in order to produce thefinal compounds of general formula (I) of substituted amidine type (cf.Diagram 1). For example, for B=thiophene, the derivatives of generalformula (II) can be condensed with S-methylthiophene thiocarboxamidehydroiodide, prepared according to a method in the literature (Ann.Chim. (1962), 7, 303-337). The condensation can be carried out byheating in an alcohol (for example in methanol or isopropanol),optionally in the presence of DMF and/or pyridine at a temperaturepreferably comprised between 20 and 100° C. for a duration generallycomprised between a few hours and overnight.

In the case where B is an amine, the final compounds of general formula(I) are guanidines. These can be prepared, for example, by thecondensation of the amines of general formula (II) with the derivativesof general formula (IV) or (IV′). The reagents of general formula (IV)in which L represents, for example, a pyrazole ring are condensed withthe amines of general formula (II) according to the conditions describedin the literature (J. Org. Chem. (1992) 57, 2497-2502) similarly for thereagents of general formula (IV′) in which L represents, for example, apyrazole ring and Gp the tBuOCO group (Tetrahedron Lett. (1993) 34 (21),3389-3392) or when L represents the —N—SO₂—CF₃ group and Gp the tBuOCOgroup (J. Org. Chem. (1998) 63, 3804-3805). During the final stage ofthe synthesis, deprotection of the guanidine function is carried out inthe presence of a strong acid such as for example trifluoroacetic acid.

Therefore the invention also relates to a process for the preparation ofa product of general formula (I) as defined previously, characterized inthat intermediate of general formula (II)A-X-Y-Φ-NH₂  (II)in which A, B, X, Y and Φ are as defined above, is reacted withintermediate of general formula (III)

in which B is as defined above and L represents a parting group, forexample an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, arylalcohol or tosyl radical.

In addition the invention relates to a process for the preparation of aproduct of general formula (I) in which B is an amine, characterized inthat intermediate of general formula (II)A-X-Y-Φ-NH₂  (II)in which A, B, X, Y and Φ are as defined above is reacted,

-   -   a) either with intermediate of general formula (IV)        in which L represents a parting group, for example an alkoxy,        alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or        tosyl radical,    -   b) or with intermediate of general formula (IV′)        in which L represents a parting group, for example an alkoxy,        alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or        tosyl radical, and Gp a protective group of carbamate type, for        example the t-butoxycarbonyl group, this reaction being        followed, in the case where reaction with the compound of        general formula (IV′) is chosen, by hydrolysis in the presence        of a strong acid, for example trifluoroacetic acid.        When -X-Y-Φ- Represents a Direct Bond:

Intermediates of general formula (II) in the particular case where-X-Y-Φ- represents a direct bond are comparable to the compounds ofgeneral formula (X), A-NH₂, described in the chapter “Synthesis ofintermediates”. In this case, these A-NH₂ amines can be directlycondensed with the derivatives of general formula (III) or (IV) asdescribed in the preceding chapter.

Preparation of the Compounds of General Formula (II):

The non-commercial intermediates of general formula (II), are obtainedeither from detachment of a protective group, or from reduction of aprecursor of nitride or nitro type, as illustrated in the synthesisdiagrams below.

Deprotection of the Amino Group:

Intermediates of general formula (II), in which A, X, Y and Φ are asdefined above, can be prepared from intermediates of general formula(V), Diagram 2, which are compounds comprising a protected amine (N=Gp′)in the form, for example, of phthalimide or 2,5-dimethylpyrrole. In thecase of phthalimides, these are deprotected in a standard fashion usinghydrazine hydrate under reflux of ethanol and in the case of pyrroles,deprotection takes place by heating in the presence of hydroxylaminehydrochloride, in order to finally produce to the primary amines ofgeneral formula (II).

Reduction of the Precursors of Azido Type:

The synthetic intermediates of general formula (VI), Diagram 3, in whichA, X, Y and Φ are as defined above, are azide derivatives which areconverted into a primary amine of general formula (II), for example,using hydrogen in the presence of Pd/C in an appropriate solvent such asethanol.

Reduction of the Precursors of Nitro Type:

The reduction of the nitro function of intermediates of general formula(VII), Diagram 4, in which A, X, Y and Φ are as defined above, isgenerally carried out by catalytic hydrogenation, in ethanol, in thepresence of Pd/C, except in the case of molecules sensitive to theseconditions where the nitro group is selectively reduced, for example, byheating the product in an appropriate solvent such as ethyl acetate witha little ethanol in the presence of SnCl₂ (J. Heterocyclic Chem. (1987),24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842), also usingSnCl₂ in the presence of Zn (Synthesis (1996), (9), 1076-1078), or usingNaBH₄—BiCl₃ (Synth. Com. (1995) 25 (23), 3799-3803) in a solvent such asethanol, or then by using Raney Ni with hydrazine hydrate added(Monatshefte für Chemie, (1995), 126, 725-732; Pharmazie (1993) 48 (11),817-820) in the case, for example, of the nitrocarbazoles.

Preparation of the Compounds of General Formula (V):

Intermediates of general formula (V), Diagram 5, contain an amineprotected in the form of phthalimide, in which X=—O—, Y=—(CH₂)_(m)— withA, R₁, R₂, R₃, R₄, R₅, W, m and Φ as defined above, can be prepared fromthe hydroxylated aromatic rings of general formula (VIII). In theparticular case of hydroxycarbazoles, the compounds of general formula(VIII) are prepared according to an experimental protocol in theliterature (J. Chem. Soc. (1955), 3475-3477; J. Med. Chem. (1964) 7,158-161) and in that of hydroxyphenothiazines the protocol is describedin J. Med. Chem. (1992) 35, 716. The compounds of general formula (VIII)are condensed with commercial halogenoalkyl-phthalimides in the presenceof a base, for example NaH, in a solvent such as DMF, in order toproduce intermediates of general formula (V).

Preparation of the Compounds of General Formula (VI):

Intermediates of general formula (VI), Diagram 6, in which A, X, Y, R₁,R₂, R₃, R₄, R₅, W, m and Φ are as defined above, are derivatives ofazido type. They are prepared in two stages from intermediates ofgeneral formula (VIII) (Diagram 5). The OH radical of the compounds ofgeneral formula (VIII) can be alkylated by dihalogenated derivatives ofdibromoalkane type, in the presence of a base, for example NaH or NaOH,in order to produce the compounds of general formula (IX) which are thensubstituted using sodium azide in DMF in order to produce intermediatesof general formula (VI).

Preparation of the Compounds of General Formula (VII):

The syntheses of the compounds of general formula (VII), which carry aterminal nitro group, in which A, X, Y and Φ are as described above, areillustrated in the following synthesis diagrams.

Syntheses of the Carboxamides of General Formula (VII):

The carboxamides of general formula (VII), Diagram 7, in which Xrepresents —NR₁₆—CO— and A, Y, Φ and R₁₆ are as defined above, areprepared by condensation of the commercial amines of general formula (X)with the commercial acids of general formula (XI). The carboxamide bondsare formed under the standard conditions of peptide synthesis (M.Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145(Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presenceof a coupling reagent such as dicyclohexylcarbodiimide (DCC),1.1′-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23),4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC or WSCI) (John Jones, The chemical synthesis ofpeptides, 54 (Clarendon Press, Oxford, 1991)). The syntheses of thenon-commercial amines of general formula (X) and the syntheses of thenon-commercial carboxylic acids of general formula (XI) are described inthe chapter Preparation of Intermediates.

The carboxamides of general formula (VII), Diagram 8, in which Xrepresents —CO—NR₁₆— and A, Y, Q, Φ and R₁₆ are as defined above, areprepared by condensation of the commercial acids of general formula(XII) with the commercial amines of general formula (XIII) or the aminesof general formula (XIV) under standard conditions for peptide synthesisdescribed previously. The syntheses of the non-commercial acids ofgeneral formula (XII) and amines of general formula (XIV) are describedin the chapter Preparation of Intermediates.

The carboxamides of general formula (VII), Diagram 9, in which Xrepresents —O—, Y represents —(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)— with A, R₁₈,m, n and Φ as defined above, are prepared by standard peptidecondensation of the acids of general formula (XI) (Diagram 7) with theamines of general formula (II), the syntheses of which have beendescribed in Diagrams 2 and 3.

Synthesis of the Amines of General Formula (VII):

The amines of general formula (VII) in which X=—NR₁₆— and Y=—(CH₂)_(m)—with A, R₁₆, m and Φ as defined above, are prepared, Diagram 10, fromthe carboxamides of general formula (VII). The reduction of thecarboxamide function is carried out in the presence of an excess (5 eq.)of diborane in THF, by heating the mixture to reflux of the solvent inorder to produce the amines of general formula (VII).

Synthesis of the Carbamates of General Formula (VII):

The carbamate derivatives of general formula (VII) in whichX=—NR₁₆—CO—O— and Y=—(CH₂)_(m)— with A, m and Φ as defined above, areprepared, Diagram 11, by condensation of an amine of general formula (X)(Diagram 7) with a commercial alcohol of general formula (XV) in thepresence of triphosgene and a base such as for exampleN,N-dimethylaniline in an inert solvent such as, for example,dichloromethane, according to a protocol described in Tetrahedron Lett.(1993) 34 (44), 7129-7132.

Synthesis of the Ureas of General Formula (VI):

The ureas of general formula (VII) in which X=—NR₁₆—CO—NR₁₇— andY=—(CH₂)_(m)— or X-Y=—NR₁₆—CO—Q— (in the case of a nitrogenousheterocycle) with A, R₁₇, m, Q and Φ as defined above, are prepared,Diagram 12, from the primary amines of general formula (X) (Diagram 7)and the amines of general formula (XIII) or (XIV) (Diagram 8) in thepresence of triphosgene and a tertiary amine, such as, for example,diisopropylethylamine, in a neutral solvent such as dichloromethane (J.Org. Chem. (1994), 59 (7), 1937-1938).

Synthesis of the Esters of General Formula (VII):

The carboxylic esters of general formula (VII) in which X=—O—CO— or—CO—O— and Y=—(CH₂)_(m)— with A, m and Φ as defined above, are preparedin a single stage from the alcohols of general formula (VIII) (Diagram5) and the carboxylic acids of general formula (XI) (Diagram 7) or theacids of general formula (XII) (Diagram 8) and the alcohols of generalformula (XV) (Diagram 11) in the presence of a coupling agent such as,for example carbonyldiimidazole or dicyclohexylcarbodiimide, in anappropriate solvent such as dichloromethane, for example.

Synthesis of the Ethers of General Formula (VII):

The ethers of general formula (VII) in which X=—O— and Y=—(CH₂)_(m)—with A, m and Φ as defined above, Diagram 14, are prepared in a singlestage by condensation of the aromatic alcohols of general formula (VIII)(Diagram 5) and the alcohols of general formula (XV) (Diagram 11) underthe standard conditions of Mitsunobu (Synthesis (1981), 1) in thepresence, for example, of diethylazodicarboxylate and tributylphosphine,in a solvent such as, for example, THF.

When X=—O—, Y is a bond and Φ=phenylene, with A and n as defined above,the ethers of general formula (VII), Diagram 15, can also be prepared ina single stage by condensation of the aromatic alcohols of generalformula (VIII) (Diagram 5) with the halogenated derivatives of generalformula (XVI), in which Hal represents a halogen atom, in the presenceof a base such as, for example, K₂CO₃, in a polar solvent such as, forexample, THF or DMF, at a reaction temperature comprised between 20 and140° C.

When X=—O— and Y=—(CH₂)_(m)—Q—(CH₂)_(n)— with A, Φ, Q and m as definedabove, the ethers of general formula (VII), Diagram 16, can also beprepared by condensation of the aromatic alcohols of general formula(VIII) (Diagram 5) with the halogenated derivatives of general formula(XVII), in which Hal represents a halogen atom, in the presence of abase such as, for example, K₂CO₃, in an inert solvent such as, forexample, CH₂Cl₂, at a temperature comprised between 40° C. and thereflux temperature of the reaction mixture. Synthesis of the compoundsof general formula (XVII) is described in the chapter Preparation ofIntermediates.

Synthesis of the Amines of General Formula (VII) by Reducing Amination:

The amines of general formula (VII), in which X=—NR₁₆—CO— andY=—(CH₂)_(m)—NR₁₈—(CH₂)_(n)— with A, Φ, R₁₆, R₁₈, m and n as definedabove, are prepared, Diagram 17, by condensation of an aldehyde ofgeneral formula (XIX) with an amine of general formula (XVIII) inreducing medium. The reaction is carried out in an alcoholic solventsuch as, for example, methanol in the presence of pulverulent 4 Åmolecular sieve, activated beforehand, and of a reducing agent such as,for example, NaBH₄ or NaBH₃CN. The syntheses of the non-commercialamines of general formula (XVIII) are described in the chapterPreparation of Intermediates.

In an analogous manner, the amines of general formula (VII), in whichX=—CH₂—NR₁₆—, with A, Y, Φ and R₁₆ as defined above, are prepared,Diagram 18, by condensation of the aldehydes of general formula (XX)with the amines of general formula (XIII) (Diagram 8) in reducing mediumunder the conditions described previously. The preparation of thenon-commercial aldehydes of general formula (XX) is described in thechapter Preparation of Intermediates.

Modification of the A Radical in the Compounds of General Formula (VII):

Intermediates of general formula (VII), in which A, X, Y, Φ, R₁, R₂, R₃,R₄ and R₅ are as described above, can be subjected to chemicalmodifications at the level of the A radical, Diagram 19, in particularat the level of the nitrogen atom which can be alkylated using anR₁₁-Hal reagent, as defined above, and in particular using methyl iodidein the presence of a base such as, for example, NaH, in an inert solventsuch as THF for example.

Preparation of the Different Synthesis Intermediates:Synthesis of Intermediates (X):

Intermediates of general formula (X) in which A is a diphenylamine (Wdoes not exist), are accessible using the methods described in theliterature (Synthesis (1990) 430; Indian J. Chem. (1981) 20B, 611-613;J. Med. Chem. (1975) 18(4), 386-391) which operate through the reductionof a nitrodiphenylamine intermediate. The reduction of the nitrofunction is carried out in a standard fashion by hydrogenation in thepresence of a catalytic quantity of Pd/C in order to access theaminodiphenylamines of general formula (X).

When A is a carbazole derivative (W then represents a direct bond), thepreparation methods for the aminocarbazoles of general formula (X)operate through the synthesis of a nitrocarbazole intermediate. Thesemethods are described in Pharmazie (1993) 48(11), 817-820; Synth.Commun. (1994) 24(1), 1-10; J. Org. Chem. (1980) 45, 1493-1496; J. Org.Chem. (1964) 29(8), 2474-2476; Org Prep. Proced. Int. (1981) 13(6),419-421 or J. Org. Chem. (1963) 28, 884. The reduction of the nitrofunction of the nitrocarbazole intermediates is, in this case,preferably carried out using hydrazine hydrate in the presence of RaneyNickel.

Intermediates of general formula (X) in which A is a phenothiazinederivative (W represents a sulphur atom), are accessible via methods inthe literature which operate through the synthesis of anitrophenothiazine derivative. In particular 3-nitrophenothiazine isdescribed in J. Org Chem. (1972) 37, 2691. The reduction of the nitrofunction in order to access the aminophenothiazines of general formula(X) is carried out in a standard fashion by hydrogenation in thepresence of a catalytic quantity of Pd/C in a solvent such as ethanol.

Synthesis of Intermediates (XI):

The syntheses of the non-commercial acids of general formula (XI), aredescribed in Diagrams 7.1 and 7.2.

In the particular case where Y=—(CH₂)_(m)—Q—(CH₂)_(n)— and Φ is aphenylene radical, with Q, m and n as defined above, the carboxylicacids of general formula (XI), Diagram 7. 1, are prepared, in 2 stages,from a heterocyclic amine of general formula (XIV) (Diagram 8), forexample 4-nitrophenylpiperazine, and of a halogenoester of generalformula (XI.1) such as for example ethyl bromoacetate. The condensationis carried out at 20° C. in the presence of a base such as, for example,triethylamine in an inert solvent such as, for example, dichloromethanein order to produce intermediates of general formula (XI.2).Saponification by LiOH at 20° C. produces the carboxylic acids ofgeneral formula (XI).

In the cases where Y=—(CH₂)_(m)—O—(CH₂)_(n)— and Φ is a phenyleneradical, with m and n as defined above, the synthesis of the carboxylicacids of general formula (XI), Diagram 7.1, operates throughcondensation of the halogenated derivatives of general formula (XI.1) onthe alcohols of general formula (XI.3) in the presence of a base suchas, for example, triethylamine or potassium carbonate, at reflux of apolar solvent such as, for example, THF or DMF. Deprotection of theester function of intermediate of general formula (XI.4) is then carriedout in a standard fashion in the presence of a base or of a strong acidfort in the case of tert-butyl esters.

The carboxylic acids of general formula (XI) in which Y=—(CH₂)_(m)— andΦ represents a substituted phenylene group, with m as defined above, areprepared in 3 stages from the commercial alcohols of general formula(XI.3), Diagram 7.2. Activation of the alcohol is carried out in astandard fashion using methane sulphonyl chloride (MsCl) in the presenceof a base such as triethylamine in an inert solvent such asdichloromethane in order to produce intermediates of general formula(XI.4). The mesylate is then displaced by sodium cyanide in DMF in orderto produce intermediates of general formula (XI.5). The nitrile functionis then hydrolyzed by heating in a mixture of ethanol and concentratedHCl in order to produce the acids of general formula (XI).

Synthesis of Intermediates (XII):

The synthesis of the carboxylic acid derivatives of the phenothiazinesof general formula (XII) is described in literature (J. Med. Chem.(1992) 35(4), 716-724).

Synthesis of Intermediates (XIV):

The non-commercial amines of general formula (XIV) defined previously,in which Q represents homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, are synthesized in threestages from the corresponding commercial diamines. The diamines areselectively mono-protected in the form of carbamate (Synthesis (1984),(12), 1032-1033; Synth. Commun. (1990), 20, (16), 2559-2564) beforereacting by nucleophilic substitution with a halogenonitrobenzene, inparticular 4-fluoronitrobenzene. The amines, which have been previouslyprotected, are released at the last stage, according to the methodsdescribed in the literature (T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)),in order to produce intermediates of general formula (XIV).

Synthesis of Intermediates (XVII):

The halogenated derivatives of general formula (XVII) definedpreviously, Diagram 16.1, are accessible in two stages from the aminesof general formula (XIII) or (XIV) (Diagram 8) and the commercialhalogenated derivatives of general formula (XVII.1). Condensation inorder to produce intermediates of general formula (XVII.2) or (XVII.3)is carried out in a standard fashion in the presence of a base such as,for example, K₂CO₃ in an appropriate inert solvent such as, for example,dichloromethane. Then the alcohol function is activated in the form of ahalogenated derivative using, for example, carbon tetrabromide in thepresence of triphenylphosphine in order to produce intermediates ofgeneral formula (XVII).

Synthesis of Intermediates (XVIII):

The amines of general formula (XVIII) defined previously, Diagram 17.1,in which A, R₁₆, R₁₈ and m are as defined above, are prepared bycondensation of the amines of general formula (X) (Diagram 7) with theprotected amino acids (Gp: protective group) of general formula(XVIII.1), under the standard conditions of peptide synthesis (see“synthesis of carboxamides” chapter). Deprotection of the amine of thecompounds of general formula (XVIII.2) is then carried out in a standardfashion according to the conditions described in literature (T. W.Greene et P. G. M. Wuts, Protective Groups in Organic Synthesis, Secondedition (Wiley-Interscience, 1991)).

Synthesis of Intermediates (XX):

Synthesis of the aldehydes of the phenothiazines of general formula (XX)defined previously is described in literature (J. Chem. Soc. (1951),1834; Bull. Soc. Chim. Fr. (1969), 1769).

Unless they are defined differently, all the technical and scientificterms used here have the same meaning as that usually understood by anordinary specialist in the field to which the invention belongs.Similarly, all publications, patent applications, patents and otherreferences mentioned here are incorporated by way of reference.

The following examples are presented to illustrate the above proceduresand should in no way be considered as restricting the scope of theinvention.

EXAMPLES Example 1

N-[4-(phenylamino)phenyl]-2-thiophene-carboximidamide hydroiodide: 1

0.92 g (5 mmol) of 4-aminodiphenylamine and 2.85 g (10 mmol) ofS-methyl-2-thiophene thiocarboximide hydroiodide in 15 ml of isopropanolare mixed together in a 50 ml flask under an argon atmosphere. Thereaction mixture is heated at 70° C. for 48 hours. The solvent ispartially evaporated under vacuum and the solid obtained is filtered andwashed several times successively with isopropanol and ethyl ether. Ayellow powder is obtained with a yield of 98%. Melting point:216.3-216.8° C.

NMR ¹H (400 MHz, DMSO d6, δ): 6.90 (m, 1H, arom.); 7.10-7.30 (m, 8H,arom.); 7.40 (m, 1H, thiophene); 8.10-8.20 (m, 2H, thiophene); 8.50 (s,1H, NH); 8.75 (s, 1H, NH⁺); 9.70 (s, 1H, NH⁺); 11.15 (s, 1H, NH⁺).

IR: ν_(C═N) (amidine): 1590 cm⁻¹.

Example 2

4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzeneacetamidehydrochloride: 2

2.1) 4-Nitro-N-[4-(phenylamino)phenyl]-benzeneacetamide:

1.84 g (10 mmol) of 4-aminodiphenylamine, 1.81 g (10 mmol) of4-nitrophenylacetic acid and 1.48 g (11 mmol) of hydroxybenzotriazole in40 ml of THF are dissolved successively in a 100 ml flask. Then 2.27 g(11 mmol) of 1,3-dicyclohexylcarbodiimide (DCC) is added and thereaction mixture is agitated for 15 hours. A precipitate ofdicyclohexylurea (DCU) forms which is filtered and rinsed with 100 ml ofethyl acetate. The filtrate is then washed successively with 50 ml of asaturated solution of Na₂CO₃, 50 ml of water, 50 ml of a molar solutionof HCl and finally 2×50 ml of salt water. The organic phase is driedover magnesium sulphate, filtered and concentrated under vacuum. Theresidue is purified rapidly on a silica gel column (eluent:heptane/ethyl acetate 1/1). The purest fractions are collected andevaporated under vacuum in order to produce a brown powder. The productis used as it is in the following stage.

NMR ¹H (100 MHz, CDCl₃, δ): 1.61 (broad s, 1H, NH); 3.82 (s, 2H, CH₂);5.70 (broad s, 1H, NH); 6.85-7.50 (m, 10H, arom., NH—CO); 7.90 (AB, 4H,Ph—NO₂).

2.2) 4-Amino-N-[4-(phenylamino)phenyl]-benzeneacetamide:

A solution of intermediate 2.1 (0.54 g, 1.54 mmol) in 40 ml of an ethylacetate/ethanol mixture (1/1) as well as 0.1 g of Pd/C at 10% areintroduced into a stainless steel autoclave equipped with a magneticstirrer. The reaction mixture is agitated under a hydrogen pressure (1.5bar) for 1 hour 30 minutes at a temperature of 20° C. The Pd/C is theneliminated by filtration and the filtrate is concentrated under vacuum.The evaporation residue is purified on a silica gel column (eluent:heptane/ethyl acetate: 4/6), the pure fractions are collected andconcentrated under vacuum. A white powder is obtained with a yield of90%. Melting point: 162-163° C.

NMR ¹H (100 MHz, CDCl₃, δ): 1.61 (broad s, 1H, NH); 3.61 (s, 2H, CH₂);3.70 (broad s, 2H, NH₂); 5.62 (broad s, 1H, NH—CO); 6.68-7.40 (m, 13H,arom.).

2.3)4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzeneacetamidehydrochloride: 2

0.44 g (1.39 mmol) of intermediate 2.2 and 0.47 g (1.67 mmol) ofS-methyl-2-thiophene thiocarboximide hydroiodide in 15 ml of isopropanolare dissolved in a 50 ml flask. The reaction mixture is agitated for 20hours at a temperature of 60° C. After evaporation of the solvent undervacuum, the residue is taken up in 100 ml of a mixture of 1N soda andethyl acetate (1/1). After decantation, the organic phase is washed with50 ml of water followed by 50 ml of salt water. The organic solution isdried over magnesium sulphate, filtered, concentrated under vacuum andthe residue is purified on a silica gel column (eluent: ethyl acetate).The pure fractions are collected and concentrated under vacuum. A whitepowder is obtained with a yield of 25%. The compound is then dissolvedin methanol and salified by adding a 1N solution of HCl in ethyl ether(1 ml). After agitation for one hour at 20° C., the reaction mixture isconcentrated under vacuum in order to produce a pale yellow powder.Melting point: the product turns into a foam.

NMR ¹H (400 MHz, DMSO d6, δ): 3.71 (s, 2H, CH₂); 4.60 (broad s, 1H, NH);6.75 (m, 1H, thiophene); 7.00 (m, 4H, arom.); 7.19 (m, 2H, arom.); 7.40(m, 3H, arom.); 7.55 (m, 4H, arom.); 8.14 (m, 2H, thiophene); 8.95(broad s, 1H, NH+); 9.86 (broad s, 1H, NH⁺); 10.41 (s, 1H, NH—CO); 11.60(broad s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1649 cm⁻¹; ν_(C═N) (amidine): 1597 cm⁻¹.

Example 3

{4-{[2-thienyl(imino)methyl]amino}phenoxy}-N-[4-(phenylamino)phenyl]-acetamidehydroiodide: 3

3.1) tertiobutyl 4-nitrophenoxyacetate:

3 g (21.6 mmol) of paranitrophenol, 8.94 g (64.8 mmol) of potassiumcarbonate and 8.42 g (43.2 mmol) of tertiobutyl bromoacetate areintroduced under a nitrogen atmosphere, into a 250 ml flask containing100 ml of THF. The reaction mixture is agitated at reflux for 2 hours.The solid is filtered and the filtrate is concentrated under reducedpressure. The residue is taken up in 50 ml of ethyl acetate and washedsuccessively with 50 ml of water and 50 ml of salt water. The organicphase is dried over sodium sulphate, filtered and evaporated undervacuum. After purification of the pure fractions on a silica gel column(eluent: ethyl acetate/heptane 1:8) and concentration under vacuum, awhite powder is obtained with yield of 50%. Melting point: 81-83° C.

NMR ¹H (100 MHz, CDCl₃, δ): 1.50 (s, 9H, 3×CH₃); 4.60 (s, 2H, CH₂); 7.57(AB, 4H, Ph—NO₂).

3.2) 4-nitrophenoxyacetic acid:

2.58 g (10.2 mmol) of intermediate 3.1 is dissolved in 45 ml ofdichloromethane in a 100 ml flask, under a nitrogen atmosphere. Themixture is cooled down to 0° C. and 7.85 ml (102 mmol) oftrifluoroacetic acid is added dropwise. The reaction mixture is agitatedfor 3 and a half hours at ambient temperature. The solution is thenconcentrated under reduced pressure. The evaporation residue is taken upin 30 ml of ethyl acetate and washed with 20 ml of water. The organicphase is dried over sodium sulphate, filtered and concentrated undervacuum. A yellow solid is obtained with a yield of 89%. The productobtained is sufficiently pure to be used directly in the followingstage. Melting point: 190-192° C.

NMR ¹H (100 MHz, CDCl₃, δ): 2.00 (broad s, 1H, COOH); 4.80 (s, 2H, CH₂);7.60 (AB, 4H, Ph—NO₂).

3.3) (4-nitrophenoxy)-N-[(4-phenylamino)phenyl]acetamide:

1.65 g (8.98 mmol) of 4-aminodiphenylaimine, 1.77 g (8.98 mmol) ofintermediate 3.2 and 1.27 g (9.42 mmol) of hydroxybenzotriazole aredissolved in 40 ml of THF in a 100 ml flask, under a nitrogenatmosphere. When all have dissolved, 1.94 g (9.42 mmol) of1,3-dicyclohexylcarbodiimide is added and the reaction medium is leftunder agitation for 15 hours. The precipitate of dicyclohexylurea formedis filtered and rinsed with ethyl acetate. The filtrate is evaporatedunder vacuum and the evaporation residue is taken up in ethyl acetate,it then forms a precipitate which is filtered and rinsed using the samesolvent. A greenish solid is obtained with a yield of 65%. The productobtained is sufficiently pure to be used directly in the followingstage. Melting point: 192-195° C.

NMR ¹H (100 MHz, CDCl₃, δ): 4.75 (s, 2H, CH₂—O); 5.70 (broad s, 1H, NH);7.10 (m, 9H, arom.); 7.85 (AB, 4H, Ph—NO₂); 8.05 (broad s, 1H, NH—CO).

3.4) (4-aminophenoxy)-N-[(4-phenylamino)phenyl]acetamide:

1 g (2.75 mmol) of intermediate 3.3 dissolved in 200 ml of a mixture ofsolvents (ethanol/dichloromethane/THF 1:1:1) and 0.1 g of Palladium oncarbon at 10% are introduced into a 300 ml autoclave. The mixture isplaced under a hydrogen pressure of 1.5 bar and agitated at ambienttemperature for 15 minutes. The catalyst is filtered off and thesolvents are concentrated under reduced pressure in order to produce apinkish beige solid with a yield of 71%. Melting point: 146-148° C.

NMR ¹H (100 MHz, CDCl₃, δ): 3.50 (broad s, 2H, NH₂); 4.50 (s, 2H,CH₂—O); 5.70 (broad s, 1H, NH); 6.70 (m, 4H, arom.); 7.10 (m, 4H,arom.); 7.25 (m, 5H, arom.); 8.20 (broad s, 1H, NH—CO).

3.5)[4-{[imino(2-thienyl)methyl]amino}phenoxy]-N-[(4-phenylamino)phenyl]acetamidehydroiodide: 3

A mixture of 0.3 g (0.9 mmol) of intermediate 3.4 in the presence of0.25 g (0.9 mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide insolution in 20 ml of isopropanol is heated at 50° C., for 15 hours. Thereaction mixture is filtered and the solid obtained is rinsed with ethylether. A yellow powder is obtained with a yield of 78%. Melting point:163-166° C.

NMR ¹H (400 MHz, DMSO d6, δ): 4.75 (s, 2H, CH₂O); 6.77 (m, 1H,thiophene); 7.04 (m, 4H, arom.); 7.19 (m, 4H, arom.); 7.40 (m, 3H,arom.); 7.50 (m, 2H, arom.); 8.12 (m, 2H, thiophene); 8.81 (broad s, 1H,NH⁺); 9.70 (broad s, 1H, NH⁺); 10.01 (s, 1H, CO—NH); 11.20 (broad s, 1H,NH⁺).

IR: ν_(C═O) (amide): 1647 cm⁻¹; ν_(C═N) (amidine): 1598 cm⁻¹.

Example 4

4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzenebutanamide:4

The experimental protocol used is the same as that described for Example2. The product is obtained in the form of the free base (white solid).Melting point: 164-167° C.

NMR ¹H (400 MHz, DMSO d6,δ): 1.86 (m, 2H, CH₂); 2.35 (m, 2H, CH₂); 2.55(m, 2H, CH₂); 6.37 (broad s, 2H, NH₂); 6.76 (m, 3H, arom.); 6.87 (m, 2H,arom.); 6.96 (m, 1H, thiophene); 7.10 (m, 3H, thiophene); 7.18 (m, 2H,arom.); 7.25 (m, 1H, arom.); 7.33 (s, 1H, NH); 7.52 (m, 1H, thiophene);7.73 (m, 1H, thiophene); 9.36 (s, 1H, NH—CO).

IR: ν_(C═O) (amide): 1627cm⁻¹; ν_(C═N) (amidine): 1591 cm⁻¹.

Example 5

4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanamidehydrochloride: 5

The experimental protocol used is the same as that described for Example2. The hydrochloride is obtained in the form of a salmon-pink powder.Melting point: 167-170° C.

NMR ¹H (400 MHz, DMSO d6, δ): 1.90 (m, 2H, CH₂); 2.35 (m, 2H, CH₂); 2.70(m, 2H, CH₂); 6.70 (m, 1H, thiophene); 7.00 (m, 4H, arom.); 7.20 (m, 2H,arom.); 7.40 (m, 5H, arom.); 7.50 (m, 2H, arom.); 8.20 (m, 2H,thiophene); 8.90 (s, 1H, NH⁺); 9.85 (s, 1H, NH⁺); 9.90 (s, 1H, NHCO);11.55 (s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1654 cm⁻¹; ν_(C═N) (amidine): 1597 cm⁻¹.

Example 6

4-{[2-thienyl(imino)methyl]amino}-N-[4-(4-methoxyphenylamino)phenyl]-benzenebutanamidehydrochloride: 6

The experimental protocol used is the same as that described forintermediate 2.3, intermediate 6.2 replacing4-amino-N-[4-(phenylamino)phenyl]-benzeneacetamide. A beige powder isobtained with a yield of 65%. Melting point: 200-202° C.

NMR ¹H (400 MHz, DMSO d6, δ): 1.91 (m, 2H, CH₂); 2.33 (m, 2H, CH₂); 2.67(mn, 2H, CH₂); 3.69 (s, 3H, O—CH₃); 4.71 (broad s, 1H, NH); 6.81-7.00(m, 6H, arom.); 7.37-7.45 (m, 7H, arom.); 8.20 (m, 2H, thiophene); 8.90(broad s, 1H, NH⁺); 9.87 (broad s, 1H, NH⁺); 9.92 (s, 1H, NH—CO); 11.67(broad s, 1H, NH⁺).

IR:ν_(C═O) (amide): 1664 cm⁻¹; ν_(C═N) (amidine): 1603 cm⁻¹.

Example 7

2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl:[4-(phenylamino)phenyl]-carbamate hydrochloride: 7

7.1) 2-(4-nitrophenyl)-ethyl [4-(phenylamino)phenyl]-carbamate:

1.18 g (3.9 mmol) of triphosgene is dissolved in 15 ml ofdichloromethane in a 250 ml flask, under argon. Using a motorizedsyringe, a solution of 2 g (12 mmol) of 4-nitrophenylethanol and 1.7 ml(13 mmol) of N,N-dimethylaniline in 40 ml of dichloromethane is addedover 1 hour. The reaction mixture is agitated for a few minutes at 20°C. before adding in one go a solution of 2.2 g (12 mmol) of4-aminodiphenylamine and 1.7 ml (13 mmol) of N,N-dimethylaniline in 40ml of dichloromethane. After agitation for one hour at 20° C., thecontents of the flask are poured into 100 ml of water. The mixture isdiluted with 100 ml of dichloromethane and agitated. The organic phaseis decanted, dried over magnesium sulphate, filtered and evaporatedunder vacuum. The solid obtained is taken up in ethyl ether, trituratedand filtered. After drying, a greenish powder is obtained with a yieldof 22%. Melting point: 146.4-148° C.

NMR ¹H (400 MHz, CDCl₃, δ): 3.10 (m, 2H, CH₂); 4.40 (m, 2H, CH₂); 5.65(s, 1H, NH); 6.50 (s, 1H, NH); 6.80-7.60 (m, 11H, arom.); 8.20 (m, 2H,arom.).

7.2) 2-(4-aminophenyl)-ethyl [4-(phenylamino)phenyl]-carbamate:

The experimental protocol used is the same as that described forintermediate 2.2, intermediate 7.1 replacing4-nitro-N-[4-(phenylamino)phenyl]-benzeneacetamide. A white solid isobtained with a yield of 48%. Melting point: 140-140.5° C.

NMR ¹H (400 MHz, DMSO d6, δ): 2.75 (m, 2H, CH₂); 4.15 (m, 2H, CH₂); 5.20(s, 2H, NH₂); 6.50 (m, 2H; arom.); 6.70 (m, 1H, arom.); 7.00 (m, 6H,arom.); 7.15 (m, 2H, arom.); 7.30 (m, 2H, arom.); 8.00 (s, 1H, NH); 9.40(s, 1H, NH).

7.3)2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl[4-(phenylamino)phenyl]-carbamatehydrochloride: 7

The experimental protocol used is the same as that described forintermediate 2.3, intermediate 7.2 replacing4-amino-N-[4-(phenylamino)phenyl]-benzeneacetamide. A white solid isobtained with a yield of 34%. Melting point: 153-159° C.

NMR ¹H (400 MHz, DMSO d6, δ): 3.00 (m, 2H, CH₂); 4.30 (m, 2H, CH₂);6.60-7.70 (m, 14H, arom.); 8.20 (m, 2H, thiophene); 8.90 (s, 1H, NH⁺);9.50 (s, 1H, NH—CO); 9.90 (s, 1H, NH⁺); 11.70 (s, 1H, NH⁺).

IR: ν_(C═O) (carbamate): 1719 cm⁻¹; ν_(C═N) (amidine): 1598 cm⁻¹.

Example 8

N-{2-{4-{[2-thienyl(imino)methyl]amino}phenyl}ethyl}-N′-[4-(phenylamino)phenyl]-ureahydrochloride: 8

8.1) N-[2-(4-nitrophenyl)-ethyl]-N′-[4-(phenylamino)phenyl]-urea:

0.5 g (1.7 mmol) of triphosgene is dissolved in 8 ml of dichloromethanein a 100 ml flask, under argon. Using a motorized syringe, a solution of0.92 g (5 mmol) of 4-aminodiphenylamine and 1.44 ml (8.2 mmol) ofdiisopropylethylamine in 15 ml of dichloromethane is added over onehour. Five minutes after the addition is finished, 1.01 g (5 mmol) of4-nitrophenethylamine hydrochloride followed by a solution of 1.44 ml(8.2 mmol) of diisopropylethylamine in 10 ml of dichloromethane areadded in a single portion. After agitation for two hours at 20° C., thereaction mixture is diluted with 50 ml of dichloromethane and 20 ml ofwater. The organic phase is decanted and rewashed with 20 ml of water.After drying over MgSO₄ and filtration, the organic solution ispartially concentrated under vacuum. The precipitate formed is collectedby filtration and rinsed with dichloromethane. A yellow solid isobtained with a yield of 40%. Melting point: 204-205° C.

NMR ¹H (100 MHz, DMSO d6, δ): 2.96 (m, 2H, CH₂); 3.50 (m, 2H, CH ₂—NH);5.78 (m, 1H, HN—CH₂); 6.45 (broad s, 1H, Ph—NH—CO); 6.72-7.49 (m, 11H,arom.); 7.81 (broad s, 1H, NH); 8.15 (m, 2H, arom.).

8.2) N-[2-(4-aminophenyl)-ethyl]-N′-[4-(phenylamino)phenyl]-urea:

A solution of intermediate 8.1 (0.68 g, 1.81 mmol) in 40 ml of aTHF/ethanol mixture (3/1) as well as 0.1 g of Pd/C at 10% is introducedinto a stainless steel autoclave equipped with a magnetic stirrer. Thereaction mixture is agitated under hydrogen pressure (1.5 bar) for 1hour at a temperature of 20° C. The Pd/C is then eliminated byfiltration and the filtrate is concentrated under vacuum. The solidobtained is washed successively with ethyl acetate and dichloromethane.A beige powder is obtained with a yield of 61%. Melting point>260° C.

NMR ¹H (100 MHz, DMSO d6, δ): 2.70 (m, 2H, CH₂); 3.40 (m, 2H, CH ₂—NH);5.18 (broad s, 2H, NH₂); 6.07 (m, 1H, HN—CH₂); 6.60-7.45 (m, 13H,arom.); 8.00 (broad s, 1H, NH); 8.41 (broad s, 1H, Ph—NH—CO).

8.3)N-{2-{4-{[2-thienyl(imino)methyl]amino}phenyl}ethyl}-N′-[4-(phenylamino)phenyl]-ureahydrochloride: 8

0.38 g (1.10 mmol) of intermediate 8.2 and 0.34 g (1.21 mmol) ofS-methyl-2-thiophene thiocarboximide hydroiodide are dissolved in 20 mlof isopropanol in a 50 ml flask. The reaction mixture is agitated for 20hours at a temperature of 60° C. After evaporation of the solvent undervacuum, the residue is taken up in 50 ml of a 1/1 mixture of a saturatedsolution of Na₂CO₃ and ethyl acetate. The reaction medium is vigorouslyagitated and after a few moments a precipitate appears. This iscollected, filtered and rinsed successively with ethyl acetate andwater. After drying, the precipitate is purified on a silica gel column(eluent THF). The pure fractions are collected and concentrated undervacuum. The solid obtained (300 mg) is redissolved in 80 ml of THF towhich 2 ml of a 1N solution of HCl in ethyl ether is added. Thehydrochloride formed precipitates, it is filtered and rinsed with THFfollowed by ethyl ether in order to produce a light grey powder. Meltingpoint: the product becomes a foam.

NMR ¹H (400 MHz, DMSO d6, δ): 2.80 (m, 2H, CH₂); 3.37 (m, 2H, CH₂); 4.46(broad s, 1H, NH); 6.40 (broad s, 1H, NH—CH₂); 6.70 (m, 1H, thiophene);6.94 (m, 4H, arom.); 7.15 (m, 2H, arom.); 7.28 (m, 2H, arom.); 7.40 (m,5H, arom.); 8.17 (m, 2H, thiophene); 8.78 (broad s, 1H, Ph—NH—CO); 8.93(broad s, 1H, NH⁺); 9.84 (broad s, 1H, NH⁺); 11.52 (broad s, 1H, NH⁺).

IR: ν_(C═O) (urea): 1654 cm⁻¹; ν_(C═N) (amidine): 1598 cm⁻¹.

Example 9

4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)phenyl]-1-piperazineacetamide hydrochloride: 9

9.1) ethyl 4-(nitrophenyl)-1-piperazine acetate:

3 g (14.5 mmol) of 1-(4-nitrophenylpiperazine) and 1.8 ml (15.9 mmol) ofbromoethyl acetate are dissolved in 60 ml of dichloromethane in a 100 mlflask. After the addition of 2.42 ml (17.4 mmol) of triethylamine, thereaction mixture is agitated, at 20° C., for one hour. The solution isthen poured into 100 ml of water and extracted with 100 ml ofdichloromethane. After decantation, the organic phase is dried overmagnesium sulphate, filtered and concentrated under vacuum. The solidobtained is taken up in ethyl ether, triturated and filtered. A yellowpowder is obtained with a yield of 89%. Melting point: 122.1-122.5° C.

NMR ¹H (400 MHz, CDCl₃, δ): 1.3 (t, 3H, CH₃, J=7 Hz); 2.75 (m, 4H,piperazine); 3.30 (s, 2H, CO—CH₂); 3.50 (m, 4H, piperazine); 4.20 (q,2H, CH ₂—CH₃, J=7 Hz); 7.45 (AB, 4H, Ph—NO₂).

9.2) 4-(nitrophenyl)-1-piperazine acetic acid:

32.4 ml of a 1M aqueous solution of LiOH is added dropwise at 20° C.into a flask containing a solution of 3.8 g (13 mmol) of intermediate9.1 in solution in 80 ml of THF. After agitation for one hour, thereaction mixture is acidified to pH=5 with a 2N solution of hydrochloricacid. The precipitate obtained is filtered and rinsed with a minimumamount of THF and water. The product is used as it is in the followingstage.

NMR ¹H (100 MHz, D₂O, δ): 3.30 (m, 4H, piperazine); 3.60 (m, 6H,piperazine+CO—CH₂); 7.45 (AB, 4H, Ph—NO₂).

9.3) 4-(4-nitrophenyl)-N-[4-(phenylamino)phenyl]-1-piperazine acetamide:

The protocol used is the same as that described for intermediate 2.1,intermediate 9.2 replacing 4-nitrophenylacetic acid. A yellow solid isobtained with a yield of 84%. Melting point: 212-213° C.

NMR ¹H (400 MHz, CDCl₃, δ): 2.80 (m, 4H, piperazine); 3.25 (s, 2H,CO—CH₂); 3.50 (m, 4H, piperazine); 5.70 (s, 1H, NH); 6.90 (m, 3H,arom.); 7.10 (m, 4H, arom.); 7.30 (m, 2H, arom.); 7.85 (AB, 4H, Ph—NO₂);8.90 (s, 1H, NHCO).

9.4) 4-(4-aminophenyl)-N-[4-(phenylamino)phenyl]-1-piperazine acetamide:

The protocol used is the same as that described for intermediate 2.2,intermediate 9.3 replacing4-nitro-N-[4-(phenylamino)phenyl]-benzeneacetamide. A brown oil isobtained with a yield of 71%.

NMR ¹H (400 MHz, CDCl₃, δ): 2.80 (m, 4H, piperazine); 3.15 (m, 4H,piperazine); 3.20 (s, 2H, CO—CH₂); 5.70 (s, 1H, NH); 6.70 (m, 2H,arom.); 6.90 (m, 3H, arom.); 7.10 (m, 4H, arom.); 7.30 (m, 2H, arom.);7.50 (m, 2H, arom.); 9.10 (s, 1H, NHCO).

9.5)4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)phenyl]-1-piperazineacetamide hydrochloride: 9

The protocol used is the same as that described for intermediate 2.3,intermediate 9.4 replacing4-amino-N-[4-(phenylamino)phenyl]-benzeneacetamide. A yellow solid isobtained with a yield of 30%. Melting point: 230-240° C.

NMR ¹H (400 MHz, DMSO d6, δ): 3.10-3.50 (m, 4H, piperazine); 3.65 (m,2H, piperazine); 3.90 (m, 2H, piperazine); 4.30 (s, 2H, CO—CH₂); 6.80(m, 1H, thiophene); 6.90-7.40 (m, 11H, arom.); 7.50 (m, 2H, arom.); 8.15(m, 2H, thiophene); 8.75 (s, 1H, NH⁺); 9.80 (s, 1H, NH⁺); 10.9 (m, 2H,NHCO+NH⁺); 11.40 (s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1680 cm⁻¹; ν_(C═N) (amidine): 1512 cm⁻¹.

Example 10

1-{[(4-phenylamino)phenylamino]carbonyl}-4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-piperazinehydrochloride: 10

The experimental protocol used is the same as that described for Example8. The product is salified under conditions which are identical tocompound 2 except that THF replaces methanol. A yellow powder isobtained. Melting point: 239-240° C.

NMR ¹H (400 MHz, DMSO d6, δ): 3.30 (broad s, 4H, piperazine); 3.70(broad s, 4H, piperazine); 5.80 (broad s, 1H, NH); 6.73 (m, 1H,thiophene); 6.98 (m, 4H, arom.); 7.17 (m, 2H, arom.); 7.28-7.37 (m, 7H,arom.); 8.16 (m, 2H, thiophene); 8.65 (broad s, 1H, Ph—NH—CO); 8.80(broad s, 1H, NH⁺); 9.80 (broad s, 1H, NH⁺); 11.52 (broad s, 1H, NH⁺).

IR: ν_(C═O) (urea): 1654 cm⁻¹; ν_(C═N) (amidine): 1597 cm⁻¹.

Example 11

4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanaminehydrochloride: 11

11.1) 4-Nitro-N-[4-(phenylamino)phenyl]-benzenebutanamine:

1.12 g (3 mmol) of 4-nitro-N-[4-(phenylamino)phenyl]-benzenebutanamide(obtained under the same conditions as intermediate 2.1) is dissolved in50 ml of anhydrous THF in a 250 ml three-necked flask under an argonatmosphere. The solution is cooled down using an ice bath, before thedropwise addition of 15 ml (15 mmol) of a solution of diborane/THF. Thereaction mixture is heated to reflux for 5 hours. After returning thetemperature to 20° C., 25 ml of an HCl solution (6N) is added slowlydropwise and the mixture is taken to reflux for 2 hours. The solution isthen cooled down using an ice bath before the addition of a 20% sodasolution until a basic pH is reached. The product is extracted usingethyl ether (2×50 ml), the organic solution is washed with salt water(2×50 ml) and dried over magnesium sulphate. After filtration andconcentration under vacuum, the residue is purified on a silica gelcolumn (eluent: heptane/AcOEt 1/1). The pure fractions are collected andevaporated under vacuum in order to produce a brown oil with a yield of28%.

NMR ¹H (400 MHz, DMSO d6, δ): 1.55 (m, 2H, CH₂); 1.71 (m, 2H, CH₂); 2.75(m, 2H, CH ₂-Arom); 2.98 (m, 2H, HN—CH ₂); 5.29 (m, 1H, NH); 6.51-7.51(m, 12H, Arom.+NH); 8.15 (m, 2H, Ph—NO₂).

11.2) 4-Amino-N-[4-(phenylamino)phenyl]-benzenebutanamine:

The experimental protocol used is the same as that described forintermediate 2.2, intermediate 11.1 replacing4-nitro-N-[4-(phenylamino)phenyl]-benzeneacetamide. A brown oil isobtained with a yield of 36%.

NMR ¹H (400 MHz, DMSO d6, δ): 1.55 (m, 4H, 2×CH₂); 2.44 (m, 2H, CH₂);2.97 (m, 2H, CH₂); 4.81 (s, 2H, NH₂); 5.27 (m, 1H, NH); 6.47-7.10 (m,13H, arom.); 7.49 (s, 1 H, NH).

11.3)4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanaminehydrochloride: 11

0.10 g (0.3 mmol) of intermediate 11.2 and 0.11 g (0.37 mmol) ofS-methyl-2-thiophene thiocarboximide hydroiodide are dissolved in 5 mlof isopropanol with 0.05 ml (0.6 mmol) of pyridine added to it, in a 50ml flask. The reaction mixture is agitated for 20 hours at a temperatureof 23° C. After evaporation of the solvent under vacuum, the residue istaken up in 25 ml of a mixture (1/1) of a saturated solution of NaHCO₃and dichloromethane. After decantation, the organic phase is washed with2×25 ml of salt water. The organic solution is dried over magnesiumsulphate, filtered, concentrated under vacuum and the residue ispurified on a silica gel column (eluent: dichloromethane+5% of ethanol).The pure fractions are collected and concentrated under vacuum. Apinkish powder is obtained which is salified by adding a 1N solution ofHCl in ethyl ether (1 ml) to the solution of the base in acetone. Afteragitation for one hour at 20° C., the reaction mixture is filtered andthe powder is washed successively with 20 ml of acetone and 20 ml ofethyl ether. Melting point: 165-166° C.

NMR ¹H (400 MHz, DMSO d6, δ): 1.71 (m, 4H, 2×CH₂); 2.66 (m, 2H, CH₂);3.20 (m, 2H, CH₂); 6.85-7.41 (m, 14H, arom.); 8.16 (m, 2H, thiophene);8.53 (broad s, 1H, NH); 8.87 (broad s, 1H, NH⁺); 9.83 (broad s, 1H,NH⁺); 11.19 (broad s, 2H, 2×NH⁺);c 11.56 (broad s, 1H, NH⁺).

IR: ν_(C═N) (amidine): 1595 cm⁻¹.

Example 12

3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenepropanamidehydrochloride: 12

12.1) 3-nitrophenylethanol mesylate:

A solution of 4.63 ml (59.8 mmol) of methane sulphonyl chloride dilutedwith 20 ml of dichloromethane is added dropwise to a solution of 10 g(59.8 mmol) of 3-nitrophenylethanol and 8.31 ml (59.8 mmol) oftriethylamine in 120 ml of dichloromethane, cooled down with an icebath. Agitation is maintained for 1 hour at 0° C. and for 2 hours at 20°C. The reaction mixture is then concentrated under vacuum and theresidue is taken up in 125 ml of ethyl acetate and 100 ml of water.After agitation and decantation, the organic phase is washedsuccessively with 100 ml of water and 100 ml of salt water. The organicsolution is dried over magnesium sulphate, filtered and concentratedunder vacuum. The evaporation residue is purified on a silica column(eluent heptane/ethyl acetate 6/4) and the pure fractions are collectedand evaporated in order to produce a yellow oil with a yield of 71%.

NMR ¹H (100 MHz, CDCl₃, δ): 3.00 (s, 3H, CH₃); 3.20 (t, 2H, CH₂, J=5.8Hz); 4.50 (t, 2H, CH₂); 7.60 (m, 2H, arom.); 8.20 (m, 2H, arom.).

12.2) 3-nitrobenzene-propanenitrile:

0.49 g (10 mmol) of NaCN is introduced in one portion into a 100 mlflask ml, under an argon atmosphere, containing a solution of 1.22 g (5mmol) of intermediate 12.1 in 20 ml of dry DMF. The reaction mixture isheated at 60° C. for 3 hours and, after allowing the temperature toreturn to 20° C., poured into 100 ml of water. The solution is extractedwith 5×50 ml of ethyl acetate, the organic phases are collected andwashed successively with 100 ml of water and 100 ml of salt water. Afterdrying over magnesium sulphate, the organic solution is concentratedunder vacuum and the residue is purified on a silica column (eluent:heptane/ethyl acetate: 7/3). The pure fractions are collected andconcentrated under vacuum in order to produce a light yellow powder witha yield of 78%. Melting point: 86-88° C.

NMR ¹H (100 MHz, CDCl₃, δ): 2.70 (t, 2H, CH₂, J=5.8 Hz); 3.10 (t, 2H,CH₂); 7.60 (m, 2H, arom.); 8.20 (m, 2H, arom.).

12.3) 3-nitrobenzene propanoic acid:

A solution of 2.33 g (19.2 mmol) of intermediate 12.2 in 100 ml of a 10%aqueous solution of HCl and 100 ml of ethanol is taken to reflux for 72hours. After allowing the temperature to return to 20° C., the reactionmixture is concentrated to dryness under vacuum. The residue is taken upin 100 ml of ethyl acetate and washed with 3×100 ml of water and with 50ml of salt water. After drying over sodium sulphate, the organicsolution is filtered and concentrated under vacuum. The evaporationresidue is purified on a silica column (eluent: heptane/ethyl acetate95/5 up to 80/20). A light yellow powder is obtained with a yield of21%. Melting point: 107-109° C.

NMR ¹H (100 MHz, CDCl₃, δ): 2.70 (m, 2H, CH₂); 3.10 (m, 2H, CH₂); 5.40(broad s, 1H, 7.50 (m, 2H, arom.); 8.10 (m, 2H, arom.).

12.4) 3-nitro-N-[4-(phenylamino)phenyl]-benzenepropanamide:

The experimental protocol used is the same as that described forintermediate 2.1, intermediate 12.3 replacing 4-nitrophenylacetic acid.A brown powder is obtained with a yield of 70%. Melting point: 130-132°C.

NMR ¹H (CDCl₃, 100 MHz, δ): 2.70 (t, 2H, CH₂, J=5.8 Hz); 3.20 (t, 2H,CH₂); 5.70 (broad s, 1H, NH); 6.90-7.60 (m, 13H, arom.).

12.5) 3-amino-N-[4-(phenylamino)phenyl]-benzenepropanamide:

The experimental protocol used is the same as that described forintermediate 2.2, intermediate 12.4 replacing4-nitro-N-[4-(phenylamino)phenyl]-benzeneacetamide. A white powder isobtained with a yield of 64%. Melting point: 164-166° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 2.80 (m, 2H, CH₂); 3.50 (m, 2H, CH₂); 5.10(broad s, 2H, NH₂); 6.50 (m, 3H, arom.); 6.80-7.45 (m, 8H, arom.); 7.60(m, 2H, arom.); 8.15 (s, 1H, NH); 9.88 (s, 1H, NH—CO).

12.6)3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenepropanamidehydrochloride: 12

The experimental protocol used is the same as that described forintermediate 2.3, intermediate 12.5 replacing4-amino-N-[4-(phenylamino)phenyl]-benzeneacetamide. After salification,a light beige powder is obtained with a yield of 78%. Melting point:228-230° C.

NMR ¹H (400 MHz, DMSO d6, δ): 2.70 (m, 2H, CH₂); 2.96 (m, 2H, CH₂); 5.20(broad s, 1H, NH); 6.74 (m, 1H, thiophene); 7.00 (m, 4H, arom.); 7.19(m, 2H, arom.); 7.29 (m, 1H, arom.); 7.39 (m, 3H, arom.); 7.47 (m, 3H,arom.); 8.18 (m, 2H, thiophene); 8.96 (broad s, 1H, NH⁺); 9.90 (broad s,1H, NH⁺); 10.07 (s, 1H, NH—CO); 11.60 (broad s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1649 cm⁻¹; ν_(C═N) (amidine): 1596 cm⁻¹.

Example 13

4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)phenyl]butanamide:13

13.1) N′-(4-methylphenyl)-1,2-benzenediamine:

The reduction of the nitro function of N-(4-methylphenyl)-2-nitroaniline(Synthesis (1990) 430) is carried out in the presence of Pd/C inethanol, under the conditions described previously for intermediate 2.2.A violet product is obtained in a semi-oil semi-crystal form with ayield of 90%.

13.2)4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)phenyl]butanamide:

The experimental protocol used is the same as that described for Example2, starting from 4-nitrophenylbutyric acid and intermediate 13.1. Theproduct is isolated in the form of a free base. White solid. Meltingpoint: 66-68° C.

Example 14

4-anilinophenyl-4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)butanoate:14

14.1) 4-anilinophenyl 4-(4-nitrophenyl)butanoate:

0.98 g (6.02 mmol) of 1,1′-carbonyldiimidazole is slowly added at 20° C.to a solution of 1.25 g (5.96 mmol) of 4-nitrophenylbutyric acid in 25ml CH₂Cl₂. The reaction mixture is agitated for 30 minutes before theaddition of 1 g (5.42 mmol) of 4-hydroxy-diphenylamine. After agitationfor 3 hours, the reaction is stopped by the addition of 3 ml of MeOH andthe solvent is evaporated under vacuum. The evaporation residue ispurified on a silica column (eluent: Heptane/AcOEt: 100/0 to 80/20). Ayellow solid is obtained with a yield of 89%.

14.2) 4-anilinophenyl4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)butanoate:

The experimental protocol used is the same as that described forintermediates 2.2 and 2.3, starting from intermediate 14.1. The productis isolated in the form of a free base. Pale yellow solid. Meltingpoint: 147-148° C.

Example 15

4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)phenyl]butanamide:15

15.1) N-{4-[4-(4-nitrophenyl)butoxy]phenyl}-N-phenylamine:

2.0 g (10.88 mmol) of 4-hydroxy-diphenylamine, 2.0 ml (12 mmol) of4-(4-nitrophenyl)-1-butanol and 1.66 ml (12 mmol) of tributylphosphineare successively introduced into a flask containing 10 ml CH₂Cl₂. 1.90ml (12 mmol) of diethylazodicarboxylate is then added dropwise and thewhole is agitated at 20° C. for 16 hours. The solvent is evaporated offunder vacuum and the residue is purified on a silica column (eluent:heptane/AcOEt: 100/0 to 80/20). The expected product is obtained in theform of a dark red oil with a yield of 35%.

15.2)N′-{4-[4-(4-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximidamide:

The experimental protocol used is the same as that described forintermediates 2.2 and 2.3, starting from intermediate 14.1. The productis isolated in the form of a free base. White solid. Melting point:120-121° C.

Example 16

N′-{4-[4-(3-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximidamide: 16

The experimental protocol used is the same as that described for Example15, starting from 3-hydroxy-diphenylamine. The product is isolated inthe form of a free base. White solid. Melting point: 73-74° C.

Example 17

N′-(9H-carbazol-3-yl)-2-thiophenecarboximidamide: 17

The experimental protocol used is the same as that described for Example1, starting from 3-aminocarbazole (Pharmazie (1993) 48(11), 817-820).The product is isolated in the form of a free base. Light beige solid.Melting point: 243-244° C.

Example 18

4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(9H-carbazol-3-yl)butanamidehydrochloride: 18

The experimental protocol used is the same as that described for Example2, starting from 3-aminocarbazole (Pharmazie (1993) 48(11), 817-820) and4-nitrophenylbutyric acid. Light beige solid. Melting point >250° C. MS:MH⁺: 452.2.

Example 19

N′-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamidehydroiodide: 19

19.1) 2-(4-nitrophenoxy)-10H-phenothiazine:

1.1 g (5.11 mmol) of 2-hydroxy-10H-phenothiazine (J. Med. Chem. (1992)35, 716), 1.34 g (9.71 mmol) of K₂CO₃ and 0.94 g (6.64 mmol) of4-fluoro-1-nitrobenzene are mixed in 25 ml anhydrous DMF in a flaskunder argon atmosphere. The reaction mixture is heated at 70° C. for 18hours. The solvent is then evaporated off under vacuum and the residueis taken up in 50 ml of AcOEt and 50 ml of water. After agitation anddecantation, the organic phase is washed with 50 ml of salt water. Theorganic solution is dried over MgSO₄, filtered and concentrated undervacuum. The residue is crystallized from diisopropyl ether. Afterdrying, a yellow solid is obtained with a yield of 83%. Melting point:210-211° C.

19.2) N′-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamidehydroiodide:

The experimental protocol used is the same as that described forintermediates 2.2 and 2.3, starting from intermediate 19.1. The expectedfinal product precipitates directly from the reaction mixture, it isisolated by filtration and washed using iPrOH. Yellow solid. Meltingpoint: 175-180° C.

Example 20

N′-{4-[(10-methyl-10H-phenothiazin-2-yl)oxy]phenyl}-2-thiophenecarboximidamidehydrochloride: 20

20.1) 10-methyl-10H-phenothiazin-2-yl 4-nitrophenylether:

0.014 g (0.58 mmol) of NaH (60%) is added to a flask under argonatmosphere, containing a solution of 0.1 g (0.29 mmol) of intermediate19.1 in 10 ml of anhydrous DMF. Agitation is maintained, at 20° C., for16 hours. 0.04 ml (0.58 mmol) of MeI is then added to the reactionmixture, under agitation at 20° C. At the end of the reaction, the wholeis poured into 50 ml of ice-cooled water and the product is extractedusing 50 ml of AcOEt. The organic phase is decanted, washed with 50 mlof salt water, dried over MgSO₄, filtered and concentrated under vacuum.The residue is purified on a silica column (eluent : heptane/AcOEt:80/20). An orange oil is obtained with a yield of 50%.

20.2)N′-{4-[(10-methyl-10H-phenothiazin-2-yl)oxy]phenyl}-2-thiophenecarboximidamidehydrochloride:

The experimental protocol used is the same as that described forintermediates 2.2 and 2.3, starting from intermediate 20.1. A whitesolid is obtained. Melting point: 256-257° C.

Example 21

4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazin-3-yl)butanamidehydrochloride: 21

21.1) 3-amino-10H-phenothiazine:

Reduction of the nitro function of 3-nitro-10H-phenothiazine (J. Org.Chem. (1972) 37, 2691) is carried out in the presence of Pd/C in anEtOH/THF mixture under the conditions described for intermediate 2.2. Agrey solid is obtained with a yield of 97%. Melting point: 150-156° C.

21.2)4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazin-3-yl)butanamidehydrochloride:

The experimental protocol used is the same as that described for Example2, starting from 4-nitrophenylbutyric acid and intermediate 21.1. Lightgreen solid. Melting point: 170-176° C.

Example 22

N′-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamidedihydrochloride: 22

22.1) 2-[4-(4-nitrophenyl)-1-piperazinyl]-1-ethanol:

7.5 g (60 mmol) of 2-bromoethanol is added, under argon atmosphere, to amixture of 10.35 g (50 mmol) of 1-(4-nitrophenyl)piperazine, 7.6 g (55mmol) of K₂CO₃ and 9 ml (65 mmol) of Et₃N in 200 ml of CH₂Cl₂. The wholeis then heated at 45° C. for 18 hours The reaction mixture is finallydiluted with 50 ml water, agitated and decanted. The organic phase iswashed with 50 ml of salt water, dried over MgSO₄, filtered andconcentrated under vacuum. The residue is crystallized from diisopropylether. A yellow solid is obtained with a yield of 89%. Melting point:98-99° C.

22.2) 1-(2-bromoethyl)-4-(4-nitrophenyl)piperazine:

8.6 g (26 mmol) of CBr₄ is added to a solution of 5 g (20 mmol) ofintermediate 22.1 in 75 ml of CH₂Cl₂. The whole is cooled using an icebath before the addition, by portions, of 6.3 g (24 mmol) oftriphenylphosphine. Agitation is maintained for 2 hours at 20° C. Afterthe addition of 50 ml of water, agitation and decantation, the organicphase is washed with 50 ml of salt water, dried over MgSO₄, filtered andconcentrated under vacuum. The evaporation residue is purified on asilica column (eluent: CH₂Cl₂/EtOH: 95/5) and finally crystallized fromethyl ether. A yellow-orange solid is obtained with a yield of 40%.Melting point: 134-135° C.

22.3) 2-{2-[4-(4-nitrophenyl)-1-piperazinyl]ethoxy}-10H-phenothiazine:

The experimental protocol used is the same as that described forintermediate 19.1, starting from intermediate 22.2. A yellow solid isobtained with a yield of 43%. Melting point: 224-225° C.

22.4)N′-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}-phenyl)-2-thiophenecarboximidamidedihydrochloride:

The experimental protocol used is the same as that described forintermediates 2.2 and 2.3 starting from intermediate 22.3. Light beigesolid. Melting point: 198-200° C.

Example 23

4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(4-toluidino)phenyl]butanamidehydrochloride: 23

23.1) N′-(4-methylphenyl)-1,4-benzenediamine:

Reduction of the nitro function of N-(4-methylphenyl)-4-nitroaniline(Indian J. Chem. (1981) 20B, 611-613) is carried out in the presence ofPd/C in ethanol, under the conditions described for intermediate 2.2. Agrey solid is obtained with a yield of 85%.

23.2)4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(4-toluidino)phenyl]butanamidehydrochloride:

The experimental protocol used is the same as that described for Example2, starting from intermediate 22.3 and 4-nitrophenylbutyric acid. Yellowsolid. Melting point: 142-145° C.

Example 24

3-anilinophenyl4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)butanoate: 24

The experimental protocol used is the same as that described for Example14, starting from 3-hydroxy-diphenylamine and 4-nitrophenylbutyric acid.White solid. Melting point: 110-112° C.

Example 25

2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(9H-carbazol-4-yloxy)ethyl]acetamidehydrochloride: 25

25.1) 3-(2-bromoethoxy)-9H-carbazole:

A mixture of 1.83 g (10 mmol) of 4-hydroxycarbazole (J. Chem. Soc.(1955), 3475-3477; J. Med. Chem. (1964) 7, 158-161), 1.08 ml (12.5 mmol)of 1,2-dibromoethane and 2.6 ml (10.5 mmol) of a 4 M aqueous solution ofNaOH in 2 ml of water is heated under reflux for 5 hours. After thetemperature returns to 20° C., the product is extracted using 2 times 30ml of CH₂Cl₂. The organic solutions collected are then successivelywashed with 20 ml of water and 20 ml of salt water. After drying overMgSO₄, filtration and concentration under vacuum, the residue ispurified on a silica column (eluent: heptane/AcOEt: 80/20). A beigepowder is obtained with a yield of 32%. Melting point: 135-136° C.

25.2) 3-(2-azidoethoxy)-9H-carbazole:

A mixture of 0.9 g (3.1 mmol) of intermediate 25.1 and 0.20 g (3.1 mmol)of NaN₃ in 10 ml of DMF is heated at 70° C. for 1 hour. The whole isthen poured into 30 ml of a mixture of water and ice. After the additionof 50 ml of AcOEt and agitation, the organic phase is decanted andwashed successively with 20 ml of water and 20 ml of salt water. Theorganic solution is then dried over Na₂SO₄, filtered and concentratedunder vacuum. After drying, a beige powder is obtained (quantitativeyield) which is used as is in the following stage.

25.3) 2-(9H-carbazol-3-yloxy)ethylamine:

A solution of intermediate 25.2 in 50 ml EtOH as well as 0.3 g Pd/C(10%) are introduced into a stainless steel autoclave equipped with amagnetic stirrer. The reaction mixture is agitated for 2 hours under 1.5bar H₂ at a temperature of 25° C. The Pd/C is then eliminated byfiltration and the filtrate is concentrated under vacuum until dryness.The residue is taken up in ethyl ether and the crystals formed arefiltered and abundantly rinsed with ethyl ether. After drying, a whitepowder is obtained with a yield of 82%. Melting point: 145-146° C.

25.4)2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(9H-carbazol-4-yloxy)ethyl]acetamidehydrochloride:

The experimental protocol used is the same as that described for Example2, starting from intermediate 25.3 and 4-nitrophenylbutyric acid. Lightbeige solid. Melting point: 233-234° C.

Example 26

N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-anilinobenzamidehydrochloride: 26

The experimental protocol used is the same as that described for Example2, starting from N-phenylanthranilic acid and 4-nitrophenethylamine.Pale yellow solid. Melting point: 163-165° C.

Example 27

N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-(2,3-dimethylanilino)benzamidehydrochloride: 27

The experimental protocol used is the same as that described for Example2, starting from mefenamic acid and 4-nitrophenethylamine. Pale yellowsolid. Melting point: 168-170° C.

Example 28

N′-{4-[4-(2-anilinobenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarboximidamidedihydrochloride: 28

The experimental protocol used is the same as that described for Example2, starting from N-phenylanthranilic acid and 4-nitrophenylpiperazine.Pale yellow solid. Melting point: 168-170° C.

Example 29

N′-(4-{4-[2-(2,3-dimethylanilino)benzoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamidedihydrochloride: 29

The experimental protocol used is the same as that described for Example2, starting from mefenamic acid and 4-nitrophenylpiperazine. Pale yellowsolid. Melting point: 166-168° C.

Example 30

4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl)butanamidehydrochloride: 30

The experimental protocol used is the same as that described for Example14, starting from 4-nitrophenylbutyric acid and 4-phenoxyphenol. Paleyellow solid. Melting point: 119-123° C.

Example 31

N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-4-(4-hydroxyphenoxy)benzamidehydrochloride: 31

The experimental protocol used is the same as that described for Example2, starting from 4-(4-hydroxyphenoxy)benzoic acid and4-nitrophenethylamine. Pale yellow solid. Melting point: 155-157° C.

Example 32

N-[2-(9H-carbazol-4-yloxy)ethyl]-2-thiophenecarboximidamide: 32

The experimental protocol used is the same as that described forintermediate 2.3, starting from intermediate 25.3. The expected productis isolated in the form of a free base. White solid. Melting point:180-181° C.

Example 33

N-[3-(9H-carbazol-4-yloxy)propyl]-2-thiophenecarboximidamide: 33

33.1) 2-[3-(9H-carbazol-4-yloxy)propyl]-1H-isoindole-1,3(2H)dione:

1 g (5.46 mmol) of 4-hydroxycarbazole (J. Chem. Soc. (1955), 3475-3477;J. Med. Chem. (1964) 7, 158-161) is added to a suspension, under argon,of 0.23 g (5.73 mmol) of NaH (60%) in 20 ml anhydrous DMF. Afteragitation for 30 minutes at 20° C., 1.46 g (5.46 mmol) of3-bromopropylphtalimide in solution in 10 ml of anhydrous DMF is addeddropwise to the reaction mixture. The whole is heated at 80° C. for 16hours. After the temperature returns to 20° C., 5 ml of water is addedand the mixture is concentrated under vacuum. The residue is taken up in300 ml of CH₂Cl₂ and the organic solution is washed successively with 50ml of 1M NaOH, 100 ml of water and 100 ml of salt water. After dryingover MgS0₄, filtration and concentration under vacuum, an oily residueis obtained which slowly crystallizes. The crystals are washed usingethyl ether. A beige solid is obtained with a yield of 40%. Meltingpoint: 171-172° C.

33.2) 3-(9H-carbazol-4-yloxy)propylamine:

A solution of 0.13 ml (3.24 mmol) hydrazine hydrate in 5 ml ethanol isadded dropwise to a solution of 0.8 g (2.16 mmol) of intermediate 33.1in 30 ml ethanol, heated to reflux. The reaction mixture is agitated andheated under reflux for 4 hours. After the temperature returns to 20°C., the product is partitioned between 100 ml of AcOEt and 50 ml of 1MNaOH. After decanting, the organic phase is washed successively with 50ml water and 50 ml salt water. The organic solution is dried overNa₂SO₄, filtered and concentrated under vacuum. A beige powder isobtained with a yield of 41%. Melting point: 146-147° C.

33.3) N-[3-(9H-carbazol-4-yloxy)propyl]-2-thiophenecarboximidamide:

The experimental protocol used is the same as that described forintermediate 2.3, starting from intermediate 33.2. The expected productis isolated in the form of a free base. Pale beige solid. Melting point:189-190° C.

Example 34

N-{4-[4-(10H-phenothiazin-2-yloxy)butyl]phenyl}-2-thiophenecarboximidamidehydroiodide: 34

The experimental protocol used is the same as that described for Example15, starting from 4-(4-nitrophenyl)-1-butanol and2-hydroxy10H-phenothiazine (J. Med. Chem. (1992) 35, 716). The expectedfinal product precipitates directly from the reaction mixture, it isisolated by filtration and washed using iPrOH. Yellow solid. Meltingpoint: 262-270° C.

Example 35

3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anilinophenyl)propanamidetrihydrochloride: 35

35.1) tert-butyl 3-(4-anilinoanilino)-3-oxopropyl carbamate:

The experimental protocol used is the same as that described forintermediate 2.1, starting from Boc-β-Alanine and 4-aminodiphenylamine.After rapid filtration on a silica column (eluent: Heptane/AcOEt: 1/1),the expected product is obtained with a quantitative yield.

35.2) 3-amino-N-(4-anilinophenyl)propanamide:

15 g (42.2 mmol) of intermediate 35.1 is dissolved in 300 ml of AcOEtand 120 ml of an aqueous 6 N HCl solution is added. The reaction mixtureis agitated vigorously, at 20° C., for 1 hour. After decantation, theaqueous phase is recovered and made basic (pH>11) by the addition of anaqueous 2 M NaOH solution. The product is then extracted using 2 times50 ml of CH₂Cl₂ and the organic phase is washed with 50 ml of saltwater. Afters drying over MgSO₄, filtration and concentration undervacuum, the residue is purified on a silica column (eluent :CH₂Cl₂/EtOH/NH₄OH (20%): 20/5/0.5). A violet powder is obtained with ayield of 73%. Melting point: 108-110° C.

35.3) N-(4-anilinophenyl)-3-[(3-nitrobenzyl)amino]propanamide:

1.40 g (5.5 mmol) of intermediate 35.2, 0.92 g (6 mmol) of3-nitrobenzaldehyde and 3 g of 4 Å pulverulent molecular sieve which hasbeen activated beforehand are added successively, under inertatmosphere, into a flask containing 100 ml anhydrous MeOH. The reactionmixture is agitated vigorously for 15 hours before the addition, byportions, of 0.24 g (6 mmol) of NaBH₄. Agitation is maintained foranother 4 hours before the addition of 10 ml of water. After a quarterof an hour, the sieve is filtered out and the reaction mixture isextracted twice with 100 ml CH₂Cl₂. The organic phase is washedsuccessively with 50 ml of water and 50 ml of salt water, dried oversodium sulphate, filtered and concentrated under vacuum. The residue ispurified on a silica column (eluent: CH₂Cl₂/EtOH: 20/1). An orange oilis obtained with a yield of 94%.

35.4) 3-[(3-aminobenzyl)amino]-N-(4-anilinophenyl)propanamide:

Reduction of the nitro function of intermediate 35.3 is carried out inthe presence of Pd/C in ethanol, under the conditions described forintermediate 2.2. After filtration of the Pd/C and concentration undervacuum, the product is directly used in the following stage.

35.5)3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anilinophenyl)propanamidetrihydrochloride:

0.50 g (1.40 mmol) of intermediate 35.4 and 0.50 g (1.75 mmol) ofS-methyl-2-thiophene thiocarboximide hydroiodide are dissolved in 15 mlisopropanol and 15 ml DMF in a 50 ml flask, in the presence of 0.11 ml(1.40 mmol) of pyridine. The reaction mixture is agitated for 20 hoursat 23° C. After evaporation of the solvent under vacuum, the residue istaken up in 100 ml of a mixture of NaOH 1N and ethyl acetate (1/1).After decantation, the organic phase is washed with 50 ml of waterfollowed by 50 ml of salt water. The organic solution is dried overmagnesium sulphate, filtered, concentrated under vacuum and the residueis purified on a silica gel column (eluent: CH₂Cl₂/EtOH/NH₄OH (20%):20/5/0.5). The pure fractions are collected and concentrated undervacuum. The compound is then dissolved in methanol and salified by theaddition of a 1N HCl solution in ethyl ether (10 ml). After agitationfor one hour at 20° C., the reaction mixture is concentrated undervacuum to produce a pale yellow powder. Melting point: 184-186° C.

Example 36

N′-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide:36

The experimental protocol used is the same as that described forintermediates 35.3, 35.4 and 35.5, starting from10H-phenothiazine-3-carbaldehyde (J. Chem. Soc. (1951), 1834 ; Bull.Soc. Chim. Fr. (1969), 1769) and 4-nitrophenethylamine. Beige foam. MS:MH⁺: 457.1.

Example 37

N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-methoxy-10H-phenothiazine-1-carboxamidehydrochloride: 37

The experimental protocol used is the same as that described for Example2, starting from 2-methoxy-10H-phenothiazine-1-carboxylic acid (J. Med.Chem. (1992) 35(4), 716-724) and 4-nitrophenethylamine. Pale yellowsolid. Melting point >200° C. (decomposition).

Example 38

N′-[4-(2-{[(2-methoxy-10H-phenothiazin-1-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide:38

38.1) 2-methoxy-10H-phenothiazine-1-carbaldehyde:

4.6 g (20 mmol) of 2-methoxy-10H-phenothiazine are dissolved, under anargon atmosphere, in a three-necked flask, containing 140 ml anhydrousethyl ether. 20 ml (50 mmol) of a solution of nBuLi (2.5 M) in hexane isthen added dropwise, at 20° C. The reaction mixture is agitated for 3hours at 20° C. before the dropwise addition of 6.2 ml (80 mmol) ofanhydrous DMF. Agitation is maintained for another 15 hours at 20° C.The whole is then poured into 150 ml ice-cooled water and the product isextracted twice using 200 ml of ethyl acetate. The organic solution iswashed with 100 ml of salt water, dried over MgSO₄, filtered andconcentrated under vacuum. The evaporation residue is taken up indiisopropyl ether, filtered and dried to produce a red solid with ayield of 30%. Melting point: 155-160° C.

38.2)N′-[4-(2-{[(2-methoxy-10H-phenothiazin-1-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide:

The experimental protocol used is the same as that described for Example36, starting from intermediate 38.1 and 4-nitrophenethylamine. Greysolid. MS: MH⁺: 487.2.

Example 39

N′-{4-[(10H-phenothiazin-2-yloxy)methyl]phenyl}-2-thiophenecarboximidamide:39

39.1) 2-[(4-nitrobenzyl)oxy]-10H-phenothiazine:

1.08 g (5 mmol) of 2-hydroxy10H-phenothiazine (J. Med. Chem. (1992) 35,716) is dissolved, under argon atmosphere, in 20 ml anhydrous THF in aflask. The solution is then cooled down to 0° C. and 0.22 g (5.5 mmol)of NaH (60%) is added by portions. After agitation for 15 minutes, 1.2 g(5.5 mmol) of 4-nitrobenzyl bromide is added by portions and thereaction mixture is agitated for 15 hours at 20° C. before being pouredinto 50 ml of ice-cooled water. The product is extracted twice with 25ml CH₂Cl₂ and the organic solution is washed successively with 25 ml ofwater and 25 ml of salt water. After drying over MgSO₄, filtration andconcentration under vacuum, the evaporation residue is purified on asilica column (eluent: CH₂Cl₂/EtOH: 99/1 to 98/2). After concentrationof the purest fractions, a maroon solid is obtained, which isrecrystallized using isopropyl acetate. A maroon solid is finallyobtained with a yield of 37%.

39.2) 4-[(10H-phenothiazin-2-yloxy)methyl]aniline:

1.02 g (4.52 mmol) of SnCl₂.2H₂O and 0.29 g (4.52 mmol) of Zn are addedsuccessively to a solution of 0.65 g (1.86 mmol) of intermediate 39.1 ina mixture of 9.3 ml of acetic acid and 1.2 ml of HCl (12 N). The wholeis agitated for 18 hours at 20° C. The reaction mixture is then madebasic by the addition of a 30% aqueous NaOH solution. The product isthen extracted twice using 50 ml of CH₂Cl₂. The organic solution iswashed with 50 ml of salt water, dried over MgSO₄, filtered andconcentrated under vacuum. The residue is purified on a silica column(eluent: Heptane/AcOEt: 1/1). A pale yellow solid is obtained with ayield of 20%. Melting point: >175° C. (decomposition).

39.3)N′-{4-[(10H-phenothiazin-2-yloxy)methyl]phenyl}-2-thiophenecarboximidamide:

The experimental protocol used is the same as that described forintermediate 2.3, starting from intermediate 39.2. Salmon-pink solid.Melting point: 105-116° C.

Pharmacological Study of the Products of the Invention

Study of the Effects on Neuronal Constitutive NO Synthase of a Rat'sCerebellum

The inhibitory activity of the products of the invention is determinedby measuring their effects on the conversion by NO synthase of[³H]L-arginine into [³H]L-citrulline according to the modified method ofBredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87: 682-685). Thecerebellums of Sprague-Dawley rats (300 g—Charles River) are rapidlyremoved, dissected at 4° C. and homogenized in a volume of extractionbuffer (HEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A 10 mg/ml, leupeptin10 mg/ml). The homogenates are then centrifuged at 21000 g for 15 min at4° C. Dosage is carried out in glass test tubes in which 100 μl ofincubation buffer containing 100 mM of HEPES (pH 7.4), 2 mM of EDTA, 2.5mM of CaCl₂, 2 mM of dithiotreitol, 2 mM of reduced NADPH and 10 μg/mlof calmodulin are distributed. 25 μl of a solution containing 100 nM of[³H]L-arginine (Specific activity: 56.4 Ci/mmol, Amersham) and 40 μM ofnon-radioactive L-arginine is added. The reaction is initiated by adding50 μl of homogenate, the final volume being 200 μl (the missing 25 μlare either water or the tested product). After 15 min, the reaction isstopped with 2 ml of stopping buffer (20 mM of HEPES, pH 5.5, 2 mM ofEDTA). After passing the samples through a 1 ml column of DOWEX resin,the radioactivity is quantified by a liquid scintillation spectrometer.The compounds of examples 3 to 5, 7, 9 to 12, 15, 16, 18, 19, 21, 22,26, 27, 30, 31 and 35 to 37 described above show an IC₅₀ lower than 3.5μM.

Study of the Effects on Lipidic Peroxidation of the Cerebral Cortex of aRat

The inhibitory activity of the products of the invention is determinedby measuring their effects on the degree of lipidic peroxidation,determined by the concentration of malondialdehyde (MDA). The MDAproduced by peroxidation of unsaturated fatty acids is a good indicationof lipidic peroxidation (H Esterbauer and K H Cheeseman, Meth. Enzymol.(1990) 186: 407-421). Male Sprague Dawley rats weighing 200 to 250 g(Charles River) were sacrificed by decapitation. The cerebral cortex isremoved, then homogenized using a Thomas potter in a 20 mM Tris-HClbuffer, pH=7.4. The homogenate was centrifuged twice at 50000 g for 10minutes at 4° C. The pellet is stored at −80° C. On the day of theexperiment, the pellet is replaced in suspension at a concentration of 1g/15 ml and centrifuged at 515 g for 10 minutes at 4° C. The supernatantis used immediately to determine the lipidic peroxidation. Thehomogenate of rat's cerebral cortex (500 μl) is incubated at 37° C. for15 minutes in the presence of the compounds to be tested or of solvent(10 μl). The lipidic peroxidation reaction is initiated by adding 50 μlof FeCl₂ at 1 mM, EDTA at 1 mM and ascorbic acid at 4 mM. Afterincubation for 30 minutes at 37° C., the reaction is stopped by adding50 μl of a solution of hydroxylated di tertio butyl toluene (BHT, 0.2%).The MDA is quantified using a colorimetric test, by reacting achromogenic reagent (R), N-methyl-2-phenylindol (650 μl) with 200 μl ofthe homogenate for 1 hour at 45° C. The condensation of an MDA moleculewith two molecules of reagent R produce a stable chromophore the maximumabsorbence wavelength of which is equal to 586 nm. (Caldwell et al.European J. Pharmacol. (1995) 285, 203-206). The compounds of Examples 1to 9, 12 to 19, 21 to 23, 30 and 35 to 37 described above show an IC₅₀lower than 30 μM.

1-14. (cancelled) 15 A compound of the formula

wherein φ is phenylene with 1 to 2 substituents selected from the groupconsisting of hydrogen, halogen, —OH, and alkyl or alkoxy of 1 to 6carbon atoms, A is

W does not exist, R₁, R₂, R₃, R₄, R₅ are individually selected from thegroup consisting of hydrogen, halogen, —OH, —CN, —NO₂, —NR₆R₇ and alkyland alkoxy of 1 to 6 carbon atoms, R₆ and R₇ are individually selectedfrom the group consisting of hydrogen, —OH, —COR₈ and alkyl or alkoxy of1 to 6 carbon atoms, R₈ is selected from the group consisting ofhydrogen, —OH, —NR₉R₁₀ and alkyl or alkoxy of 1 to 6 carbon atoms, R₉and R₁₀ are individually selected from the group consisting of hydrogen,—OH and alkyl of 1 to 6 carbon atoms, R₁₁ is selected from the groupconsisting of hydrogen, —OH, —COR₁₂ and alkyl or alkoxy of 1 to 6 carbonatoms, R₁₂ is selected from the group consisting of hydrogen, —OH andalkyl of 1 to 6 carbon atoms, B is selected from the group consisting of—CH₂—NO₂, alkyl of 1 to 6 carbon atoms, —NR₁₃R₁₄ and unsubstituted andsubstituted carbocyclic aryl and heterocyclic aryl of 5 to 6 ringmembers containing 1 to 4 heteroatoms containing 1 to 4 heteroatomsselected from the group consisting of oxygen, sulfur and nitrogen, thearyl substituents being selected from the group consisting of alkyl,alkenyl and alkoxy of up to 6 carbon atoms, R₁₃ and R₁₄ are individuallyselected from the group consisting of hydrogen, —CN, —NO₂ and alkyl of 1to 6 carbon atoms or together with the nitrogen form a non-aromaticheterocycle of 5 to 6 ring members selected from the group consisting of—CH₂—, —NH—, —O— and S—, X is selected from the group consisting of abond, —(CH₂)_(k)—NR₁₆—, —O—, —S—, —CO—, —NR₁₆—CO—, —CO—NR₁₆—, —O—CO—,—CO—O—, —NR₁₆—CO—O— and —NR₁₆—CO—NR₁₇—, k is 0 or 1, Y represents a bondor a radical chosen from the —(CH₂)_(m)—, (CH₂)_(m)—O—(CH₂)_(n)—,—(CH₂)_(m)—S—(CH₂)_(n)—, —(CH)_(m)—NR₁₈(CH₂)_(n)—,—(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)—, —(CH₂)_(m)—CO—NR₁₈—(CH₂)_(n)—,—(CH₂)_(m)—Q—(CH₂)_(n)-radicals, Q is selected from the group consistingof piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-oxypiperidine and 4-aminopiperidine, m and nare individually integers from 0 to 6, R₁₆, R₁₇ and R₁₈ are individuallya hydrogen atom or alkyl of 1 to 6 carbon atoms and its pharmaceuticallyacceptable salt with acids or bases. 16 The compound of claim 15 whereinA is

R₁, R₂, R₃, R₄, R₅ are individually selected from the group consistingof hydrogen, halogen, —OH and alkyl and alkoxy of 1 to 6 carbon atoms,R₁₁ is hydrogen atom or alkyl of 1 to 6 carbon atoms, B is a substitutedor unsubstituted carbocyclic aryl or heterocyclic aryl of 5 to 6 ringmembers containing 1 to 4 heteroatoms selected from the group consistingof oxygen, sulfur and nitrogen, the aryl substituents being selectedfrom the group consisting of alkyl, alkenyl and alkoxy of up to 6 carbonatoms, W does not exist, X is selected from the group consisting of abond, —(CH₂)_(k)—NR₁₆—, —O—, —S—, —CO—, —NR₁₆—CO—, —CO—NR₁₆—, —O—CO—,—CO—O—, —NR₁₆—CO—O— and —NR₁₆—CO—NR₁₇—, k is 0 or 1, Y is selected fromthe group consisting of a bond, —(CH₂)_(m—, —(CH) ₂)_(m)—O—(CH₂)_(n)—,—(CH₂)_(m)—S—(CH)₂)_(n)—, —(CH₂)_(m)—NR₁₈—(CH₂)_(n)—,—(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)—, —(CH₂)_(m)—CO—NR₁₈—(CH₂)_(n)— and—(CH₂)_(m)—Q—(CH₂)_(n)—, Q is selected from the group consisting ofpiperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine,4-oxypiperazine or 4-aminopiperidine and m and n are integers from 0 to6. 17 The compound of claim 15 wherein B is selected from the groupconsisting of thiophene, furan, pyrrole and thiazole. 18 The compound ofclaim 15 wherein A is

R₁, R₂, R₃, R₄ and R₅ are individually selected from hydrogen, —OH andalkyl and alkoxy of 1 to 6 carbon atoms, R₁₁ is hydrogen or methyl, B isselected from the group consisting of unsubstituted or substitutedphenyl, thiophene, furan, pyrrole and thiazole, the substituents beingat least one member of the group consisting of alkyl, alkenyl and alkoxyof up to 6 carbon atoms, W does not exist, X is selected from the groupconsisting of a bond, —(CH₂)_(k)—NR₁₆—, —O—, —S—, —CO—, —NR₁₆—CO—,—CO—NR₁₆—, —O—CO—, —CO—O—, —NR₁₆—CO—O— and —NR₁₆—CO—NR₁₇—, k is 0 or 1,Y is selected from the group consisting of a bond, —(CH₂)_(m)—,—(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,—(CH₂)_(m)—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)—,—(CH₂)_(m)—CO—NR₁₈—(CH₂)_(n))— and —(CH₂)_(m)—Q—(CH₂)_(n)—, Q isselected from the group consisting of piperazine, homopiperazine,2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or4-aminopiperidine and m and n are integers from 0 to
 6. 19 The compoundof claim 15 wherein A is

R₁, R₂, R₃, R₄, R₅ are individually hydrogen or methyl, R₁₁ is hydrogenor methyl, B is thiophene, W does not exist, X does not exist or isselected from the group consisting of —(CH₂)_(k)—NR₁₆—, —O—, —S—, —CO—,—NR₁₆—CO—, —CO—NR₁₆—, —O—CO—, —CO—O—, —NR₁₆—CO—O— and —NR₁₆—CO—NR₁₇—, kis 0 or 1, Y is selected from the group consisting of —(CH₂)_(m)—,—(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,—(CH₂)_(m)—NR₁₈—(CH₂)_(n)—, —(CH₂)_(m)—NR₁₈—CO—(CH₂)_(n)—,—(CH₂)_(m)—CO—NR₁₈—(CH₂)_(n)— and —(CH₂)_(m)—Q—(CH₂)_(n)—, Q ispiperazine, m and n are integers from 0 and 6 and R₁₆, R₁₇ and R₁₈ arehydrogen. 20 A compound of claim 15 which is4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl)butanamidehydrochloride orN-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-4-(4-hydroxyphenoxy)benzamidehydrochloride. 21 A compound of claim 20 in the form of itshydrochloride salt. 22 A composition for inhibiting NO synthase and/orlipidic peroxidation comprising an effective amount of a compound ofclaim 15 and an inert pharmaceutical carrier. 23 A method of inhibitingNO synthase in warm-blooded animals comprising administration to saidpatient of a NO synthase inhibitory amount of a compound of generalformula (I) as defined in claim 15 or a pharmaceutically acceptable saltof said compound. 24 A method of inhibiting lipidic peroxidation in apatient in need thereof comprising administration to said patient of alipidic peroxidation inhibitory amount of a compound of general formula(I) as defined in claim 15 or of a pharmaceutically acceptable salt ofsaid compound. 25 A method of inhibiting both NO synthase and lipidicperoxidation in a patient in need thereof comprising administration tosaid patient of a compound of general formula (I) as defined in claim 15or of a pharmaceutically acceptable salt of said compound, in an amountsufficient to inhibit both NO synthase and lipidic peroxidation.